The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM.

PubMed

Koopmeiners, Joseph S; Wey, Andrew

2017-01-01

The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD.

Escalator design features evaluation

NASA Technical Reports Server (NTRS)

Zimmerman, W. F.; Deshpande, G. K.

1982-01-01

Escalators are available with design features such as dual speed (90 and 120 fpm), mat operation and flat steps. These design features were evaluated based on the impact of each on capital and operating costs, traffic flow, and safety. A human factors engineering model was developed to analyze the need for flat steps at various speeds. Mat operation of escalators was found to be cost effective in terms of energy savings. Dual speed operation of escalators with the higher speed used during peak hours allows for efficient operation. A minimum number of flat steps required as a function of escalator speed was developed to ensure safety for the elderly.

Escalator Design Features Evaluation

DOT National Transportation Integrated Search

1982-05-01

This study provides an evaluation of the effectiveness of several special design features associated with escalators in rail transit systems. The objective of the study was to evaluate the effectiveness of three escalator design features: (1) mat ope...

Escalated conflict in a social hierarchy

PubMed Central

Cant, M.A; English, S; Reeve, H.K; Field, J

2006-01-01

Animals that live in cooperative societies form hierarchies in which dominant individuals reap disproportionate benefits from group cooperation. The stability of these societies requires subordinates to accept their inferior status rather than engage in escalated conflict with dominants over rank. Applying the logic of animal contests to these cases predicts that escalated conflict is more likely where subordinates are reproductively suppressed, where group productivity is high, relatedness is low, and where subordinates are relatively strong. We tested these four predictions in the field on co-foundress associations of the paper wasp Polistes dominulus by inducing contests over dominance rank experimentally. Subordinates with lower levels of ovarian development, and those in larger, more productive groups, were more likely to escalate in conflict with their dominant, as predicted. Neither genetic relatedness nor relative body size had significant effects on the probability of escalation. The original dominant emerged as the winner in all except one escalated contest. The results provide the first evidence that reproductive suppression of subordinates increases the threat of escalated conflict, and hence that reproductive sharing can promote stability of the dominant–subordinate relationship. PMID:17015353

Escalation research: Providing new frontiers for applying behavior analysis to organizational behavior

PubMed Central

Goltz, Sonia M.

2000-01-01

Decision fiascoes such as escalation of commitment, the tendency of decision makers to “throw good money after bad,” can have serious consequences for organizations and are therefore of great interest in applied research. This paper discusses the use of behavior analysis in organizational behavior research on escalation. Among the most significant aspects of behavior-analytic research on escalation is that it has indicated that both the patterns of outcomes that decision makers have experienced for past decisions and the patterns of responses that they make are critical for understanding escalation. This research has also stimulated the refinement of methods by researchers to better assess decision making and the role reinforcement plays in it. Finally, behavior-analytic escalation research has not only indicated the utility of reinforcement principles for predicting more complex human behavior but has also suggested some additional areas for future exploration of decision making using behavior analysis. PMID:22478347

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group.

PubMed

Borchmann, Peter; Haverkamp, Heinz; Lohri, Andreas; Mey, Ulrich; Kreissl, Stefanie; Greil, Richard; Markova, Jana; Feuring-Buske, Michaela; Meissner, Julia; Dührsen, Ulrich; Ostermann, Helmut; Keller, Ulrich; Maschmeyer, Georg; Kuhnert, Georg; Dietlein, Markus; Kobe, Carsten; Eich, Hans; Baues, Christian; Stein, Harald; Fuchs, Michael; Diehl, Volker; Engert, Andreas

2017-04-01

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPP escalated group and 93·0% (89·4-96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPP escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

PubMed

Takahashi, Aki; Lee, Ray X; Iwasato, Takuji; Itohara, Shigeyoshi; Arima, Hiroshi; Bettler, Bernhard; Miczek, Klaus A; Koide, Tsuyoshi

2015-04-22

Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons. Copyright © 2015 the authors 0270-6474/15/356452-12$15.00/0.

Willingness to trade-off: An intermediate factor in patient decision-making regarding escalating care.

PubMed

Seng, Elizabeth K; Grinberg, Amy S; Fraenkel, Liana

2018-01-01

This study aimed to evaluate treatment necessity, treatment concern, and willingness to engage in decisional trade-offs in the context of treatment escalation decision-making. Participants ( n  = 147) recruited online were randomized to read a vignette about escalating care in psoriasis in a 2 (high treatment concern vs moderate treatment concern) × 2 (high perceived treatment necessity vs moderate perceived treatment necessity) design. High treatment concern was associated with choosing to defer treatment escalation and being unwilling to engage in decisional trade-offs if disease risk changed. Results highlight the importance of treatment concern and willingness trade-off in treatment escalation decision-making.

Willingness to trade-off: An intermediate factor in patient decision-making regarding escalating care

PubMed Central

Seng, Elizabeth K; Grinberg, Amy S; Fraenkel, Liana

2018-01-01

This study aimed to evaluate treatment necessity, treatment concern, and willingness to engage in decisional trade-offs in the context of treatment escalation decision-making. Participants (n = 147) recruited online were randomized to read a vignette about escalating care in psoriasis in a 2 (high treatment concern vs moderate treatment concern) × 2 (high perceived treatment necessity vs moderate perceived treatment necessity) design. High treatment concern was associated with choosing to defer treatment escalation and being unwilling to engage in decisional trade-offs if disease risk changed. Results highlight the importance of treatment concern and willingness trade-off in treatment escalation decision-making. PMID:29662681

De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study.

PubMed

Moraes, Rafael Barberena; Guillén, Julián Alberto Viteri; Zabaleta, William Javier Castillo; Borges, Flavia Kessler

2016-09-01

To evaluate the prevalence of antibiotic de-escalation in patients diagnosed with severe sepsis or septic shock at a public academic tertiary hospital and to evaluate antibiotic adequacy and culture positivity. The prevalence of antibiotic de-escalation, the adequacy of antibiotic treatment and the rates of culture positivity were analyzed in patients with severe sepsis and septic shock between April and December 2013 at an intensive care unit in a tertiary university hospital. Among the 224 patients included in the study, de-escalation was appropriate in 66 patients (29.4%) but was implemented in 44 patients (19.6%). Among the patients who underwent de-escalation, half experienced narrowing of the antimicrobial spectrum. The mortality rate was 56.3%, with no differences between the patients with or without de-escalation (56.8% versus 56.1%; p = 0.999) nor in the length of hospital stay. Empirical antibiotic therapy was appropriate in 89% of cases. Microorganisms were isolated from total cultures in 30% of cases and from blood cultures in 26.3% of cases. The adequacy rate of empirical antibiotic therapy was high, reflecting an active institutional policy of monitoring epidemiological profiles and institutional protocols on antimicrobial use. However, antibiotic de-escalation could have been implemented in a greater number of patients. De-escalation did not affect mortality rates.

Clinical benefits of antimicrobial de-escalation in adults with community-onset monomicrobial Escherichia coli, Klebsiella species and Proteus mirabilis bacteremia.

PubMed

Lee, Ching-Chi; Wang, Jiun-Ling; Lee, Chung-Hsun; Hung, Yuan-Pin; Hong, Ming-Yuan; Tang, Hung-Jen; Ko, Wen-Chien

2017-09-01

The clinical benefits of an antimicrobial de-escalation strategy were compared with those of a no-switch strategy in bacteremic patients. Adults with community-onset monomicrobial Escherichia coli, Klebsiella species and Proteus mirabilis bacteremia treated empirically using broad-spectrum beta-lactams, including third-generation cephalosporins (GCs), fourth-GC or carbapenems, were treated definitively with first- or second-GCs (de-escalation group), the same regimens as empirical antibiotics (no-switch group), or antibiotics with a broader-spectrum than empirical antibiotics (escalation group). The eligible 454 adults were categorized as the de-escalation (231 patients, 50.9%), no-switch (177, 39.0%), and escalation (46, 10.1%) groups. Patients with de-escalation therapy were more often female, had less critical illness and fatal comorbidity, and had a higher survival rate than patients in the other two groups. After propensity score matching in the de-escalation and no-switch groups, critical illness at onset (Pitt bacteremia score ≥ 4; 16.5% vs. 12.7%; P = 0.34) or day 3 (2.5% vs. 2.5%; P = 1.00), fatal comorbidity (16.5% vs. 21.5%; P = 0.25), time to defervescence (4.6 vs. 4.7 days; P = 0.89), hospital stays (11.5 vs. 10.3 days; P = 0.13) and 4-week crude mortality rate (4.4% vs. 4.4%; P = 1.00) were similar. However, lower antibiotic cost (mean: 212.1 vs. 395.6 US$, P <0.001) and fewer complications of bloodstream infections due to resistant pathogens (0% vs. 5.1%, P = 0.004) were observed in the de-escalation group. De-escalation to narrower-spectrum cephalosporins is safe and cost-effective for adults with community-onset EKP bacteremia stabilized by empirical broad-spectrum beta-lactams. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

[A comparative study of the effectiveness and tolerability of a procedure involving slow dose-escalation of rivastigmine in patients with mild or moderate Alzheimer-type dementia: the SCALEX study].

PubMed

Agüera-Ortiz, L F; Ramos-García, M; Gobartt, A L

To determine and to compare the tolerability and effectiveness of a slow escalation of the dose of rivastigmine in patients with Alzheimer's disease with respect to using it with a faster escalation. We conducted a multi-centre, naturalistic, open-label, randomised trial with 429 hospital outpatients diagnosed with Alzheimer-type dementia (according to DSM-IV and NINCDS-ADRA criteria) and in whom treatment with rivastigmine was clinically indicated. Two study groups were established: slow escalation and fast escalation (in accordance with usual clinical practice); effectiveness and tolerability variables were analysed in the two groups, as was the proportion of patients who reached therapeutic doses (> 6 mg/day). The scores obtained on the CGI, MMSE, NPI and Barthel index scales were analysed, together with adverse events and reactions concerning spontaneous communication, and scores on the UKU scale. The slow escalation group displayed slightly higher percentages of sub-therapeutic anticipated interruptions than the fast escalation group (chi-square test; p < 0.05). On comparing the two treatment groups, no statistically significant differences were observed for the evolution of the scores on the different scales of effectiveness; no statistically significant differences were found between the two groups in the safety and tolerability analyses (chi-square test, exact test; p > 0.05) for most of the parameters that were studied (adverse reactions in spontaneous communication and the modified UKU scale). Slow escalation of the dose of rivastigmine did not display greater effectiveness or tolerability in comparison to an escalation applied in accordance with usual clinical practice.

Contest experience and body size affect different types of contest decisions.

PubMed

Chen, Yu-Ju; Hsu, Yuying

2016-11-01

This study examined the relative importance of contest experience and size differences to behavioral decisions over the course of contests. Using a mangrove rivulus fish, Kryptolebias marmoratus, we showed that although contest experience and size differences jointly determined contest outcomes, they affected contestants' interactions at different stages of contests. Contest experience affected behavioral decisions at earlier stages of contests, including the tendency and latency to launch attacks, the tendency to escalate contests into mutual attacks and the outcome of non-escalated contests. Once contests were escalated into mutual attacks, the degree of size difference affected the fish's persistence in escalation and chance of winning, but contest experience did not. These results support the hypothesis that contest experience modifies individuals' estimation of their fighting ability rather than their actual strength. Furthermore, (1) in contests between two naïve contestants, more than 60 % of fish that were 2-3 mm smaller than their opponent escalated the contest to physical fights, even though their larger opponents eventually won 92 % of escalated fights and (2) fish with a losing experience were very likely to retreat in the face of an opponent 2-3 mm smaller than them without escalating. The result that a 2-3 mm size advantage could not offset the influence of a losing experience on the tendency to escalate suggests that, as well as depending on body size, the fish's physical strength is influenced by other factors which require further investigation.

29 CFR 1917.116 - Elevators and escalators.

Code of Federal Regulations, 2011 CFR

2011-07-01

... or more floors of a structure. The term excludes such devices as conveyors, tiering or piling... vicinity of the escalator or be available at the terminal. (f) Elevator landing openings shall be provided... landing, to prevent employees from falling into the shaft. (g) The elevator's or escalator's maximum load...

41 CFR 102-85.55 - What are the terms and conditions included in an OA?

Code of Federal Regulations, 2011 CFR

2011-01-01

... Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 85-PRICING... used; (d) Operating costs and escalations; (e) One time charges; e.g., lump sum payments by the customer; (f) Real estate tax and escalations; (g) Parking and escalations; (h) Additional/reduced services...

41 CFR 102-85.55 - What are the terms and conditions included in an OA?

Code of Federal Regulations, 2012 CFR

2012-01-01

... Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 85-PRICING... used; (d) Operating costs and escalations; (e) One time charges; e.g., lump sum payments by the customer; (f) Real estate tax and escalations; (g) Parking and escalations; (h) Additional/reduced services...

41 CFR 102-85.55 - What are the terms and conditions included in an OA?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 85-PRICING... used; (d) Operating costs and escalations; (e) One time charges; e.g., lump sum payments by the customer; (f) Real estate tax and escalations; (g) Parking and escalations; (h) Additional/reduced services...

41 CFR 102-85.55 - What are the terms and conditions included in an OA?

Code of Federal Regulations, 2014 CFR

2014-01-01

... Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 85-PRICING... used; (d) Operating costs and escalations; (e) One time charges; e.g., lump sum payments by the customer; (f) Real estate tax and escalations; (g) Parking and escalations; (h) Additional/reduced services...

A Comparison of Escalating versus Fixed Reinforcement Schedules on Undergraduate Quiz Taking

ERIC Educational Resources Information Center

Mahoney, Amanda

2017-01-01

Drug abstinence studies indicate that escalating reinforcement schedules maintain abstinence for longer periods than fixed reinforcement schedules. The current study evaluated whether escalating reinforcement schedules would maintain more quiz taking than fixed reinforcement schedules. During baseline and for the control group, bonus points were…

41 CFR 102-85.55 - What are the terms and conditions included in an OA?

Code of Federal Regulations, 2010 CFR

2010-07-01

... Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 85-PRICING... used; (d) Operating costs and escalations; (e) One time charges; e.g., lump sum payments by the customer; (f) Real estate tax and escalations; (g) Parking and escalations; (h) Additional/reduced services...

The support-control continuum: An investigation of staff perspectives on factors influencing the success or failure of de-escalation techniques for the management of violence and aggression in mental health settings.

PubMed

Price, Owen; Baker, John; Bee, Penny; Lovell, Karina

2018-01-01

De-escalation techniques are recommended to manage violence and aggression in mental health settings yet restrictive practices continue to be frequently used. Barriers and enablers to the implementation and effectiveness of de-escalation techniques in practice are not well understood. To obtain staff descriptions of de-escalation techniques currently used in mental health settings and explore factors perceived to influence their implementation and effectiveness. Qualitative, semi-structured interviews and Framework Analysis. Five in-patient wards including three male psychiatric intensive care units, one female acute ward and one male acute ward in three UK Mental Health NHS Trusts. 20 ward-based clinical staff. Individual semi-structured interviews were digitally recorded, transcribed verbatim and analysed using a qualitative data analysis software package. Participants described 14 techniques used in response to escalated aggression applied on a continuum between support and control. Techniques along the support-control continuum could be classified in three groups: 'support' (e.g. problem-solving, distraction, reassurance) 'non-physical control' (e.g. reprimands, deterrents, instruction) and 'physical control' (e.g. physical restraint and seclusion). Charting the reasoning staff provided for technique selection against the described behavioural outcome enabled a preliminary understanding of staff, patient and environmental influences on de-escalation success or failure. Importantly, the more coercive 'non-physical control' techniques are currently conceptualised by staff as a feature of de-escalation techniques, yet, there was evidence of a link between these and increased aggression/use of restrictive practices. Risk was not a consistent factor in decisions to adopt more controlling techniques. Moral judgements regarding the function of the aggression; trial-and-error; ingrained local custom (especially around instruction to low stimulus areas); knowledge of the patient; time-efficiency and staff anxiety had a key role in escalating intervention. This paper provides a new model for understanding staff intervention in response to escalated aggression, a continuum between support and control. It further provides a preliminary explanatory framework for understanding the relationship between patient behaviour, staff response and environmental influences on de-escalation success and failure. This framework reveals potentially important behaviour change targets for interventions seeking to reduce violence and use of restrictive practices through enhanced de-escalation techniques. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism.

PubMed

Han, Xiao; DeBold, Joseph F; Miczek, Klaus A

2017-09-01

A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined. The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice. First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration. These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.

Understanding the Emotional Aspects of Escalation of Commitment: The Role of Negative Affect

ERIC Educational Resources Information Center

Wong, Kin Fai Ellick; Yik, Michelle; Kwong, Jessica Y. Y.

2006-01-01

Despite the importance of understanding the emotional aspects of organizational decision making, prior research has paid scant attention to the role of emotion in escalation of commitment. This article attempts to fill this gap by examining the relationship between negative affect and escalation of commitment. Results showed that regardless of…

Water and Wastewater Annual Price Escalation Rates for Selected Cities across the United States

DOE Office of Scientific and Technical Information (OSTI.GOV)

None, None

Pacific Northwest National Laboratory conducted this study for the Federal Energy Management Program to identify trends in annual water and wastewater price escalation rates across the United States. This study can be used to inform the selection of an appropriate escalation rates for inclusion in LCCA.

Effect of climate-related mass extinctions on escalation in molluscs

NASA Astrophysics Data System (ADS)

Hansen, Thor A.; Kelley, Patricia H.; Melland, Vicky D.; Graham, Scott E.

1999-12-01

We test the hypothesis that escalated species (e.g., those with antipredatory adaptations such as heavy armor) are more vulnerable to extinctions caused by changes in climate. If this hypothesis is valid, recovery faunas after climate-related extinctions should include significantly fewer species with escalated shell characteristics, and escalated species should undergo greater rates of extinction than nonescalated species. This hypothesis is tested for the Cretaceous-Paleocene, Eocene-Oligocene, middle Miocene, and Pliocene-Pleistocene mass extinctions. Gastropod and bivalve molluscs from the U.S. coastal plain were evaluated for 10 shell characters that confer resistance to predators. Of 40 tests, one supported the hypothesis; highly ornamented gastropods underwent greater levels of Pliocene-Pleistocene extinction than did nonescalated species. All remaining tests were nonsignificant. The hypothesis that escalated species are more vulnerable to climate-related mass extinctions is not supported.

Attribution Bias and Overconfidence in Escalation of Commitment: The Role of Desire to Rectify Past Outcomes

ERIC Educational Resources Information Center

Tine, Delilah Castillo

2013-01-01

Escalation of commitment is the voluntary continuation of investing resources into what appears to be a failing course of action whose outcome is uncertain. Investigation into the escalation of commitment phenomenon is important to organizations because such behavior could result in grave economic loss. This research investigates two cognitive…

14 CFR Appendix A to Part 1215 - Estimated Service Rates in 1997 Dollars for TDRSS Standard Services (Based on NASA Escalation...

Code of Federal Regulations, 2014 CFR

2014-01-01

... Services (Based on NASA Escalation Estimate) Time: Project conceptualization (at least two years before... TDRSS Standard Services (Based on NASA Escalation Estimate) A Appendix A to Part 1215 Aeronautics and... the service requirements by NASA Headquarters, communications for the reimbursable development of a...

14 CFR Appendix A to Part 1215 - Estimated Service Rates in 1997 Dollars for TDRSS Standard Services (Based on NASA Escalation...

Code of Federal Regulations, 2013 CFR

2013-01-01

... Services (Based on NASA Escalation Estimate) Time: Project conceptualization (at least two years before... TDRSS Standard Services (Based on NASA Escalation Estimate) A Appendix A to Part 1215 Aeronautics and... the service requirements by NASA Headquarters, communications for the reimbursable development of a...

Development and Analysis of Security Policies in Security Enhanced Android

DTIC Science & Technology

2012-12-01

Privilege - Escalation Attacks on Android ,” Proc. 19th Annual...Services, Bethesda, MD, 2011, pp. 239–252. 98 [43] L. Davi, et al. “ Privilege Escalation Attacks on Android ,” Proc. 13th Int. Conf. on Information...TaintDroid. XManDroid dynamically analyzes applications’ transitive permission usage in order to prevent application-level privilege escalation attacks

Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

NASA Astrophysics Data System (ADS)

Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

2017-03-01

Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

High and escalating levels of cocaine intake are dissociable from subsequent incentive motivation for the drug in rats.

PubMed

Allain, Florence; Bouayad-Gervais, Karim; Samaha, Anne-Noël

2018-01-01

Taking high and increasing amounts of cocaine is thought to be necessary for the development of addiction. Consequently, a widely used animal model of drug self-administration involves giving animals continuous drug access during long sessions (LgA), as this produces high and escalating levels of intake. However, human cocaine addicts likely use the drug with an intermittent rather than continuous pattern, producing spiking brain cocaine levels. Using an intermittent-access (IntA) cocaine self-administration procedure in rats, we studied the relationship between escalation of cocaine intake and later incentive motivation for the drug, as measured by responding under a progressive ratio schedule of cocaine reinforcement. First, under IntA, rats escalated their cocaine use both within and between sessions. However, escalation did not predict later incentive motivation for the drug. Second, incentive motivation for cocaine was similar in IntA-rats limited to low- and non-escalating levels of drug intake (IntA-Lim) and in IntA-rats that took high and escalating levels of drug. Finally, IntA-Lim rats took much less cocaine than rats given continuous drug access during each self-administration session (LgA-rats). However, IntA-Lim rats later responded more for cocaine under a progressive ratio schedule of reinforcement. Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern-even in small amounts-is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.

Evaluation of empiric antibiotic de-escalation in febrile neutropenia.

PubMed

Kroll, Amanda L; Corrigan, Patricia A; Patel, Shejal; Hawks, Kelly G

2016-10-01

Up until 2010, the recommended duration of empiric broad-spectrum antibiotics for febrile neutropenia was until absolute neutrophil count (ANC) recovery. An updated guideline on the use of antimicrobial agents in neutropenic patients with cancer indicates that patients who have completed an appropriate treatment course of broad-spectrum antibiotics, with resolution of signs and symptoms of infection but persistent neutropenia, can be de-escalated to oral fluoroquinolone prophylaxis until ANC recovery. The primary objective of this retrospective investigation was to evaluate the safety and efficacy of de-escalating broad-spectrum antibiotics in patients remaining neutropenic after at least 14 days of empiric broadspectrum antibiotics for febrile neutropenia compared to patients continuing broad-spectrum antibiotics until ANC recovery. There were 16 patients (61.5%) in the comparator group who met the primary endpoint of remaining afebrile and without escalation of antibiotics for at least 72 hours after 14 days of broad-spectrum antibiotics and 21 patients (80.7%) in the de-escalation group who met the primary endpoint of remaining afebrile and without reinitiation of broad-spectrum antibiotics for at least 72 hours after de-escalation to levofloxacin therapy (p = 0.11). Mean total duration of broad-spectrum antibiotic therapy was 23.5 ± 1.5 days in the comparator group versus 22.2 ± 1.43 days in the de-escalation group (p = 0.39). Results of this investigation indicate that broad-spectrum antibiotics can be safely de-escalated to levofloxacin prophylaxis prior to ANC recovery in select patients. This practice may decrease the duration of broad-spectrum antibiotic exposure and associated complications. © The Author(s) 2015.

Individualized Radiation Dose Escalation Based on the Decrease in Tumor FDG Uptake and Normal Tissue Constraints Improve Survival in Patients With Esophageal Carcinoma.

PubMed

Ma, Jinbo; Wang, Zhaoyang; Wang, Chengde; Chen, Ercheng; Dong, Yaozong; Song, Yipeng; Wang, Wei; You, Dong; Jiang, Wei; Zang, Rukun

2017-02-01

To determine whether individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor and normal tissue constraints can improve survival in patients with esophageal carcinoma. From August 2005 to December 2010, 112 patients with squamous esophageal carcinoma were treated with radical concurrent chemoradiation. Patients received positron emission tomography-computer tomography scan twice, before radiation and after radiation dose of 50.4 Gy. All patients were noncomplete metabolic response groups according to the Response Evaluation Criteria in solid tumors. Only 52 patients with noncomplete metabolic response received individualized dose escalation based on tumor and normal tissue constraints. Survival and treatment failure were observed and analyzed using SPSS (13.0). The rate of complete metabolic response for patients with noncomplete metabolic response after dose escalation reached 17.3% (9 of 52). The 2-year overall survival rates for patients with noncomplete metabolic response in the conventional and dose-escalation groups were 20.5% and 42.8%, respectively( P = .001). The 2-year local control rates for patients were 35.7% and 76.2%, respectively ( P = .002). When patients were classified into partial metabolic response and no metabolic response, 2-year overall survival rates for patients with partial metabolic response were significantly different in conventional and dose-escalation groups (33.8% vs 78.4%; P = .000). The 2-year overall survival rates for patients with no metabolic response in two groups (8.6% vs 15.1%) did not significantly differ ( P = .917). Individualized radiation dose escalation has the potential to improve survival in patients with esophageal carcinoma according to increased rate of complete metabolic response. However, further trials are needed to confirm this and to identify patients who may benefit from dose escalation.

The practices of expert psychiatric nurses: accompanying the patient to a calmer personal space.

PubMed

Johnson, M E; Hauser, P M

2001-01-01

The focus of the care of potentially aggressive psychiatric patients has been on the use of seclusion and restraints. Recent concerns, however, about the potential for patient injury have made it imperative that nurses use alternative methods to calm patients who are escalating. Little is known about how expert nurses de-escalate the escalating patient. The purpose of this interpretive phenomenological study was to uncover and describe the knowledge embedded in the stories of psychiatric nurses who are skilled in the practices of de-escalating an escalating patient. Twenty registered nurses were interviewed using an unstructured format. The analysis of the data revealed that these nurses were skilled at noticing the patient, reading the situation and the patient, knowing where the patient was on the continuum, understanding the meaning of the behavior, knowing what the patient needed, connecting with the patient, and matching the intervention with the patient's needs.

Treat-early and treat-mild: role of fast vs. slow escalation of headaches.

PubMed

Ng-Mak, D S; Ma, L; Hu, X H; Chen, Y-T

2009-04-01

This prospective, multi-center, observational study aimed to examine patients' early treatment decision process. Specifically, we assessed if the association between mild headache pain at treatment initiation and early treatment differed by the speed of headache escalation. Patients (n = 168) were instructed to collect information on their headache experience during the study period via an electronic diary over 30 consecutive days after enrollment. At the time of treatment, patients who treated early were 2.3 times as likely to experience mild headache pain as those who treated late. Controlling for the effect of escalation of headache, patients who treated early were three times as likely to report mild headache pain at dosing as those who treated late. The interaction between fast escalation of headache and mild pain was not statistically significant. Early treatment is associated with mild pain, regardless of the speed of headache escalation.

77 FR 42353 - Escalate Capital Partners SBIC I, L.P.; Notice Seeking Exemption Under Section 312 of the Small...

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2012-07-18

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42 CFR 405.1106 - Where a request for review or escalation may be filed.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Where a request for review or escalation may be filed. 405.1106 Section 405.1106 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF... § 405.1016, the request for escalation must be filed with both the ALJ and the MAC. The appellant must...

42 CFR 405.1106 - Where a request for review or escalation may be filed.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Where a request for review or escalation may be filed. 405.1106 Section 405.1106 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF... § 405.1016, the request for escalation must be filed with both the ALJ and the MAC. The appellant must...

Determinants of escalating costs in low risk workers' compensation claims.

PubMed

Bernacki, Edward J; Yuspeh, Larry; Tao, Xuguang

2007-07-01

To identify and quantify attributes that lead to unanticipated cost escalation in workers' compensation claims. We constructed four claim categories: low initial reserve/low cost, migrated catastrophic (low initial reserve/high cost), high initial reserve/low cost, and catastrophic (high initial reserve/high cost). To assess the attributes associated with the increased cost of migrated catastrophic claims, we analyzed 36,329 Louisiana workers' compensation claims in the four categories over a 5-year period. In the 729 claims initially thought to be low-cost claims (migrated catastrophic), the most significant predictors for cost escalation were attorney involvement and claim duration, followed by low back disorder, married/single/divorced status, male gender, small company size, high premium, reporting delays, and older age. These injuries accounted for 2% of all claims but 32.3% of the costs. Accelerated escalation of costs occurred late in the claim cycle (2 years). Certain attributes, particularly attorney involvement and claim duration, are associated with unanticipated cost escalation in a small number of claims that drastically affect overall losses. The results of this study suggest that these cases may be identified and addressed before rapid escalation occurs.

Destined to die but not to wage war: how existential threat can contribute to escalation or de-escalation of violent intergroup conflict.

PubMed

Jonas, Eva; Fritsche, Immo

2013-10-01

War means threat to people's lives. Research derived from terror management theory (TMT) illustrates that the awareness of death leads people to defend cultural ingroups and their worldviews to attain a sense of symbolic immortality and thereby buffer existential anxiety. This can result in hostile effects of mortality salience (MS), such as derogation of outgroup members, prejudice, stereotyping, aggression, and racism, which, in turn, can lead to the escalation of violent intergroup conflict and, thus, the escalation of war. Yet, escalation of destructive conflict following MS is not automatic. Instead, research on TMT suggests that MS does not necessarily result in conflict and intolerance but can also foster positive tendencies, such as intergroup fairness or approval of pacifism, depending on how existential threat is perceived, whether the need for symbolic self-transcendence is satisfied, which social norms are salient, and how social situations are interpreted. In the present article, we review current TMT research with the aim of reconciling the seemingly contradictory findings of hostile and peaceful reactions to reminders of death. We present a terror management model of escalation and de-escalation of violent intergroup conflicts, which takes into account the interaction between threat salience and features of the social situation. We also discuss possible intervention strategies to override detrimental consequences of existential threat and argue that war is not the inevitable consequence of threat. PsycINFO Database Record (c) 2013 APA, all rights reserved

Reply to: Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection.

PubMed

Coburn, Brian W; Michaud, Kaleb; Bergman, Debra A; Mikuls, Ted R

2018-05-08

We thank Dr. Bredemeier for his comments regarding our manuscript on allopurinol dose escalation and mortality. He raises important evidence to consider in support of an interesting hypothesis that dose escalation may be unnecessary for allopurinol's cardiovascular (CV) protection and may actually be related to adverse CV outcomes. While we agree that evidence exists suggesting that low doses of allopurinol may be sufficient for CV protection, we believe that the studies cited highlight a number of areas where knowledge gaps remain which preclude any definitive conclusions about the effect of dose escalation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Escalation: How Much is Enough?

NASA Technical Reports Server (NTRS)

Butts, Glenn

2007-01-01

Determining the escalation percentage to an estimate is often the subject of fierce debate. Cost increases are determined by dynamic relati onships between many factors, including acts of nature, interest rate s, oil prices, global commodity markets, wars, wage rates, and the ov erall health of the economy, as well as supply and demand for the required goods or services. How much escalation is enough? Are the recen t price increases temporary aberrations, or will they continue to pla gue us? This paper examines historical escalation rates, as well as i ndications of trends. Various analysis methods -- Monte Carlo simulations, neural networks, trend impact analysis, and the Delphi method -- are examined in an attempt to determine future trends.

Validation and testing of the Acceptability E-scale for Web-based patient-reported outcomes in cancer care

PubMed Central

Tariman, Joseph D.; Berry, Donna L.; Halpenny, Barbara; Wolpin, Seth; Schepp, Karen

2010-01-01

The performance of the Acceptability E-scale was tested in a sample of 627 adult and older adult patients from various oncology clinics who completed an electronic symptoms survey. The revised Acceptability E-scale has strong psychometric properties and can be useful in assessing the acceptability and usability of computerized health-related programs in oncology and other health population. PMID:20974066

Subthreshold depressive disorder in adolescents: predictors of escalation to full-syndrome depressive disorders.

PubMed

Klein, Daniel N; Shankman, Stewart A; Lewinsohn, Peter M; Seeley, John R

2009-07-01

Subthreshold depressive disorder is one of the best established risk factors for the onset of full-syndrome depressive disorders. However, many youths with subthreshold depressive disorder do not develop full-syndrome depression. We examined predictors of escalation to full-syndrome depressive disorders in a community sample of 225 adolescents with subthreshold depressive disorder. Criteria for subthreshold depressive disorder were an episode of depressed mood or loss of interest or pleasure lasting at least 1 week and at least two of the seven other DSM-IV-associated symptoms for major depression. Participants were assessed four times from mid-adolescence to age 30 years using semistructured diagnostic interviews. The estimated risk for escalation to full-syndrome depressive disorders was 67%. Five variables accounted for unique variance in predicting escalation: severity of depressive symptoms, medical conditions/symptoms, history of suicidal ideation, history of anxiety disorder, and familial loading for depression. Adolescents with three or more risk factors had an estimated 90% chance of escalating to full-syndrome depressive disorder, compared with 47% of adolescents with fewer than three risk factors. These data may be useful in identifying a subgroup of youths with subthreshold depressive disorder who are at especially high risk for escalating to full-syndrome depressive disorders.

Subthreshold Depressive Disorder in Adolescents: Predictors of Escalation to Full-Syndrome Depressive Disorders

PubMed Central

KLEIN, DANIEL N.; SHANKMAN, STEWART A.; LEWINSOHN, PETER M.; SEELEY, JOHN R.

2010-01-01

Objectives Subthreshold depressive disorder is one of the best established risk factors for the onset of full-syndrome depressive disorders. However, many youths with subthreshold depressive disorder do not develop full-syndrome depression. We examined predictors of escalation to full-syndrome depressive disorders in a community sample of 225 adolescents with subthreshold depressive disorder. Method Criteria for subthreshold depressive disorder were an episode of depressed mood or loss of interest or pleasure lasting at least 1 week and at least two of the seven other DSM-IV-associated symptoms for major depression. Participants were assessed four times from mid-adolescence to age 30 years using semistructured diagnostic interviews. Results The estimated risk for escalation to full-syndrome depressive disorders was 67%. Five variables accounted for unique variance in predicting escalation: severity of depressive symptoms, medical conditions/symptoms, history of suicidal ideation, history of anxiety disorder, and familial loading for depression. Adolescents with three or more risk factors had an estimated 90% chance of escalating to full-syndrome depressive disorder, compared with 47% of adolescents with fewer than three risk factors. Conclusions These data may be useful in identifying a subgroup of youths with subthreshold depressive disorder who are at especially high risk for escalating to full-syndrome depressive disorders. PMID:19465876

Conflict escalation in paediatric services: findings from a qualitative study

PubMed Central

Forbat, Liz; Teuten, Bea; Barclay, Sarah

2015-01-01

Objective To explore clinician and family experiences of conflict in paediatric services, in order to map the trajectory of conflict escalation. Design Qualitative interview study, employing extreme-case sampling. Interviews were analysed using an iterative thematic approach to identify common themes regarding the experience and escalation of conflict. Participants Thirty-eight health professionals and eight parents. All participants had direct experience of conflict, including physical assault and court proceedings, at the interface of acute and palliative care. Setting Two teaching hospitals, one district general hospital and two paediatric hospices in England, in 2011. Results Conflicts escalate in a predictable manner. Clearly identifiable behaviours by both clinicians and parents are defined as mild, moderate and severe. Mild describes features like the insensitive use of language and a history of unresolved conflict. Moderate involves a deterioration of trust, and a breakdown of communication and relationships. Severe marks disintegration of working relationships, characterised by behavioural changes including aggression, and a shift in focus from the child's best interests to the conflict itself. Though conflicts may remain at one level, those which escalated tended to move sequentially from one level to the next. Conclusions Understanding how conflicts escalate provides clinicians with a practical, evidence-based framework to identify the warning signs of conflict in paediatrics. PMID:25940425

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

Escalation to Major Depressive Disorder among Adolescents with Subthreshold Depressive Symptoms: Evidence of Distinct Subgroups at Risk

PubMed Central

Hill, Ryan M.; Pettit, Jeremy W.; Lewinsohn, Peter M.; Seeley, John R.; Klein, Daniel N.

2014-01-01

Background The presence of subthreshold depressive symptoms (SubD) in adolescence is associated with high prospective risk of developing Major Depressive Disorder (MDD). Little is known about variables that predict escalation from SubD to MDD. This study used a longitudinal prospective design in a community sample of adolescents to identify combinations of risk factors that predicted escalation from SubD to MDD. Methods Classification tree analysis was used to identify combinations of risk factors that improved the sensitivity and specificity of prediction of MDD onset among 424 adolescents with a lifetime history of SubD. Results Of the 424, 144 developed MDD during the follow-up period. Evidence for multiple subgroups was found: Among adolescents with poor friend support, the highest risk of escalation was among participants with lifetime histories of an anxiety or substance use disorder. Among adolescents with high friend support, those reporting multiple major life events in the past year or with a history of an anxiety disorder were at highest risk of escalation. Limitations Study findings may not inform prevention efforts for individuals who first develop SubD during adulthood. This study did not examine the temporal ordering of predictors involved in escalation from SubD to MDD. Conclusions Adolescents with a history of SubD were at highest risk of escalation to MDD in the presence of poor friend support and an anxiety or substance use disorder, or in the presence of better friend support, multiple major life events, and an anxiety disorder. Findings may inform case identification approaches for adolescent depression prevention programs. PMID:24655777

Change in Visual Field Progression Following Treatment Escalation in Primary Open-angle Glaucoma.

PubMed

Aptel, Florent; Bron, Alain M; Lachkar, Yves; Schweitzer, Cédric

2017-10-01

To evaluate the effect of treatment escalation on the rate of visual field progression in patients with primary open-angle glaucoma (POAG). Multicenter database study. We reviewed the electronic records of 171 patients with POAG under medical hypotensive treatment who underwent 5 consecutive visits 6 months apart before and after medical treatment escalation or additive laser trabeculoplasty. We calculated the rate of visual field progression (mean deviation change per year) before and after treatment escalation. The mean duration of follow-up was 5.1±0.5 years and the mean number of visual field examinations was 10.2±0.2. In 139 eyes with medical treatment escalation, the rate of progression was significantly reduced [from -0.57 to -0.29 dB/y; P=0.022; intraocular pressure (IOP) reduction 11.1%]. In detail, the rate of progression was significantly reduced after escalation from mono to dual therapy, dual to triple therapy, and from mono to triple therapy (-0.35 to -0.24 dB/y, P=0.018; -1.01 to -0.48 dB/y, P=0.038; -1.04 to -0.35 dB/y, P=0.020, respectively). In 32 eyes with additive laser trabeculoplasty, the rate of progression was significantly reduced (-0.60 to -0.24 dB/y; P=0.014; IOP reduction 9.4%). Medical treatment escalation or additive laser trabeculoplasty significantly reduced the rate of visual field progression in POAG. Larger IOP reduction has a greater probability of reducing glaucoma progression.

Developmental trends in alcohol use initiation and escalation from early- to middle-adolescence: Prediction by urgency and trait affect

PubMed Central

Spillane, Nichea S.; Merrill, Jennifer E.; Jackson, Kristina M.

2016-01-01

Studies on adolescent drinking have not always been able to distinguish between initiation and escalation of drinking, because many studies include samples in which initiation has already occurred; hence initiation and escalation are often confounded. The present study draws from a dual-process theoretical framework to investigate: if changes in the likelihood of drinking initiation and escalation are predicted by a tendency towards rash action when experiencing positive and negative emotions (positive and negative urgency); and whether trait positive and negative affect moderate such effects. Alcohol naïve adolescents (n=944; age: M=12.16, SD=.96; 52% female) completed 6 semi-annual assessments of trait urgency and affect (wave-1) and alcohol use (waves 2–6). A two-part random-effects model was used to estimate changes in the likelihood of any alcohol use vs. escalation in the volume of use amongst initiators. Main effects suggest a significant association between positive affect and change in level of alcohol use amongst initiators, such that lower positive affect predicted increased alcohol involvement. This main effect was qualified by a significant interaction between positive urgency and positive affect predicting changes in the escalation of drinking, such that the effect of positive urgency was augmented for those high on trait positive affect, though only at extremely high levels of positive affect. Results suggest risk factors in the development of drinking depend on whether initiation or escalation is investigated. A more nuanced understanding of the early developmental phases of alcohol involvement can inform prevention and intervention efforts. PMID:27031086

Care planning for aggression management in a specialist secure mental health service: An audit of user involvement.

PubMed

Hallett, Nutmeg; Huber, Jörg W; Sixsmith, Judith; Dickens, Geoffrey L

2016-12-01

This paper describes an audit of prevention and management of violence and aggression care plans and incident reporting forms which aimed to: (i) report the compliance rate of completion of care plans; (ii) identify the extent to which patients contribute to and agree with their care plan; (iii) describe de-escalation methods documented in care plans; and (iv) ascertain the extent to which the de-escalation methods described in the care plan are recorded as having been attempted in the event of an incident. Care plans and incident report forms were examined for all patients in men's and women's mental health care pathways who were involved in aggressive incidents between May and October 2012. In total, 539 incidents were examined, involving 147 patients and 121 care plans. There was no care plan in place at the time of 151 incidents giving a compliance rate of 72%. It was documented that 40% of patients had contributed to their care plans. Thematic analysis of de-escalation methods documented in the care plans revealed five de-escalation themes: staff interventions, interactions, space/quiet, activities and patient strategies/skills. A sixth category, coercive strategies, was also documented. Evidence of adherence to de-escalation elements of the care plan was documented in 58% of incidents. The reasons for the low compliance rate and very low documentation of patient involvement need further investigation. The inclusion of coercive strategies within de-escalation documentation suggests that some staff fundamentally misunderstand de-escalation. © 2016 Australian College of Mental Health Nurses Inc.

SU-C-BRB-02: Automatic Planning as a Potential Strategy for Dose Escalation for Pancreas SBRT?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, S; Zheng, D; Ma, R

Purpose: Stereotactic body radiation therapy (SBRT) has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process, and may impede further escalation of the prescription dose. The present study evaluates the potential of an automatic planning system as a dose escalation strategy. Methods: Ten pancreatic cancer patients treated with SBRT were studied retrospectively. SBRT was delivered over 5 consecutive fractions with 6 ∼ 8Gy/fraction. Two plans were generated by Pinnacle Auto-Planning with the original prescription and escalated prescription, respectively. Escalated prescriptionmore » adds 1 Gy/fraction to the original prescription. Manually-created planning volumes were excluded in the optimization goals in order to assess the planning efficiency and quality simultaneously. Critical organs with closest proximity were used to determine the plan normalization to ensure the OAR sparing. Dosimetric parameters including D100, and conformity index (CI) were assessed. Results: Auto-plans directly generate acceptable plans for 70% of the cases without necessity of further improvement, and two more iterations at most are necessary for the rest of the cases. For the pancreas SBRT plans with the original prescription, autoplans resulted in favorable target coverage and PTV conformity (D100 = 96.3% ± 1.48%; CI = 0.88 ± 0.06). For the plans with the escalated prescriptions, no significant target under-dosage was observed, and PTV conformity remains reasonable (D100 = 93.3% ± 3.8%, and CI = 0.84 ± 0.05). Conclusion: Automatic planning, without substantial human-intervention process, results in reasonable PTV coverage and PTV conformity on the premise of adequate OAR sparing for the pancreas SBRT plans with escalated prescription. The results highlight the potential of autoplanning as a dose escalation strategy for pancreas SBRT treatment planning. Further investigations with a larger number of patients are necessary. The project is partially supported by Philips Medical Systems.« less

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PubMed

Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

2011-05-01

To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

PubMed

Maráz, Anikó; Cserháti, Adrienn; Uhercsák, Gabriella; Szilágyi, Éva; Varga, Zoltán; Révész, János; Kószó, Renáta; Varga, Linda; Kahán, Zsuzsanna

2018-03-15

In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

PubMed

Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

2015-01-01

The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

Improving Escalation of Care: Development and Validation of the Quality of Information Transfer Tool.

PubMed

Johnston, Maximilian J; Arora, Sonal; Pucher, Philip H; Reissis, Yannis; Hull, Louise; Huddy, Jeremy R; King, Dominic; Darzi, Ara

2016-03-01

To develop and provide validity and feasibility evidence for the QUality of Information Transfer (QUIT) tool. Prompt escalation of care in the setting of patient deterioration can prevent further harm. Escalation and information transfer skills are not currently measured in surgery. This study comprised 3 phases: the development (phase 1), validation (phase 2), and feasibility analysis (phase 3) of the QUIT tool. Phase 1 involved identification of core skills needed for successful escalation of care through literature review and 33 semistructured interviews with stakeholders. Phase 2 involved the generation of validity evidence for the tool using a simulated setting. Thirty surgeons assessed a deteriorating postoperative patient in a simulated ward and escalated their care to a senior colleague. The face and content validity were assessed using a survey. Construct and concurrent validity of the tool were determined by comparing performance scores using the QUIT tool with those measured using the Situation-Background-Assessment-Recommendation (SBAR) tool. Phase 3 was conducted using direct observation of escalation scenarios on surgical wards in 2 hospitals. A 7-category assessment tool was developed from phase 1 consisting of 24 items. Twenty-one of 24 items had excellent content validity (content validity index >0.8). All 7 categories and 18 of 24 (P < 0.05) items demonstrated construct validity. The correlation between the QUIT and SBAR tools used was strong indicating concurrent validity (r = 0.694, P < 0.001). Real-time scoring of escalation referrals was feasible and indicated that doctors currently have better information transfer skills than nurses when faced with a deteriorating patient. A validated tool to assess information transfer for deteriorating surgical patients was developed and tested using simulation and real-time clinical scenarios. It may improve the quality and safety of patient care on the surgical ward.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Aim Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. PMID:27274277

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Observational evidence that urbanisation and neighbourhood deprivation are associated with escalation in chronic pharmacological pain treatment: a longitudinal population-based study in the Netherlands.

PubMed

Leue, Carsten; Buijs, Servaas; Strik, Jacqueline; Lousberg, Richel; Smit, Jasper; van Kleef, Maarten; van Os, Jim

2012-01-01

To examine, in the light of the association between urban environment and poor mental health, whether urbanisation and neighbourhood deprivation are associated with analgesic escalation in chronic pharmacological pain treatment and whether escalation is associated with prescriptions of psychotropic medication. Longitudinal analysis of a population-based routine dispensing database in the Netherlands. Representative sample of pharmacies, covering 73% of the Dutch nationwide medication consumption in the primary care and hospital outpatient settings. 449 410 patients aged 15-85 years were included, of whom 166 374 were in the Starter group and 283 036 in the Continuation group of chronic analgesic treatment. Escalation of analgesics (ie, change to a higher level of analgesic potency, classified across five levels) in association with urbanisation (five levels) and dichotomous neighbourhood deprivation was analysed over a 6-month observation period. Ordered logistic multivariate model evaluating analgesic treatment. In both Starter and Continuation groups, escalation was positively associated with urbanisation in a dose-response fashion (Starter group: OR (urbanisation level 1 compared with level 5): 1.24, 95% CI 1.18 to 1.30; Continuation group: OR 1.18, 95% CI 1.14 to 1.23). An additional association was apparent with neighbourhood deprivation (Starter group: OR 1.07, 95% CI 1.02 to 1.11; Continuation group: OR 1.04, 95% CI 1.01 to 1.08). Use of somatic and particularly psychotropic co-medication was associated with escalation in both groups. Escalation of chronic analgesic treatment is associated with urban and deprived environments and occurs in a context of adding psychotropic medication prescriptions. These findings suggest that pain outcomes and mental health outcomes share factors that increase risk and remedy suffering.

Escalation to Major Depressive Disorder among adolescents with subthreshold depressive symptoms: evidence of distinct subgroups at risk.

PubMed

Hill, Ryan M; Pettit, Jeremy W; Lewinsohn, Peter M; Seeley, John R; Klein, Daniel N

2014-04-01

The presence of subthreshold depressive symptoms (SubD) in adolescence is associated with high prospective risk of developing Major Depressive Disorder (MDD). Little is known about variables that predict escalation from SubD to MDD. This study used a longitudinal prospective design in a community sample of adolescents to identify combinations of risk factors that predicted escalation from SubD to MDD. Classification tree analysis was used to identify combinations of risk factors that improved the sensitivity and specificity of prediction of MDD onset among 424 adolescents with a lifetime history of SubD. Of the 424, 144 developed MDD during the follow-up period. Evidence for multiple subgroups was found: among adolescents with poor friend support, the highest risk of escalation was among participants with lifetime histories of an anxiety or substance use disorder. Among adolescents with high friend support, those reporting multiple major life events in the past year or with a history of an anxiety disorder were at highest risk of escalation. Study findings may not inform prevention efforts for individuals who first develop SubD during adulthood. This study did not examine the temporal ordering of predictors involved in escalation from SubD to MDD. Adolescents with a history of SubD were at highest risk of escalation to MDD in the presence of poor friend support and an anxiety or substance use disorder, or in the presence of better friend support, multiple major life events, and an anxiety disorder. Findings may inform case identification approaches for adolescent depression prevention programs. Copyright © 2014 Elsevier B.V. All rights reserved.

Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.

PubMed

Kepka, Lucyna; Tyc-Szczepaniak, Dobromira; Bujko, Krzysztof

2009-07-01

To determine the efficacy of accelerated hypofractionated three-dimensional conformal radiotherapy (3D-CRT) with dose-per-fraction escalation for treatment of stage III non-small cell lung cancer (NSCLC). Between 2001 and 2007, 173 patients with stage III NSCLC were treated using accelerated 3D-CRT and the simultaneous boost technique. Initially, the total dose of 56.7 Gy (including 39.9 Gy to the elective area) was delivered over 4 weeks in fractions of 2.7 Gy (1.9 Gy to the elective area). The dose-per-fraction escalation study commenced after the outcomes of 70 patients had been evaluated. The dose per fraction was increased from 2.7 through 2.8 Gy (level 1 escalation) to 2.9 Gy (level 2 escalation); the total dose increased, respectively, from 56.7 Gy through 58.8 Gy to 60.9 Gy. The dose to the elective area and the overall treatment time remained unchanged. Fit patients received two to three courses of chemotherapy before radiotherapy. The 2- and 3-year overall survival rates were 32 and 19%, respectively (median survival = 17 months). Of the patients, 7% had grade III acute esophageal toxicity and 6% had grade III or greater late pulmonary toxicity. Two of the nine patients who received the level 2 escalation (60.9 Gy) died of pulmonary toxicity. The study was terminated at a dose of 58.8 Gy and this schema was adopted as the institutional policy for treatment of stage III NSCLC. Although dose escalation with accelerated hypofractionated 3D-CRT was limited, the results and toxicity profiles obtained using this technique are promising.

Dangerous Thresholds. Managing Escalation in the 21st Century

DTIC Science & Technology

2008-01-01

Escalation in the 21st Century Forrest E . Morgan n Karl P. Mueller Evan S. Medeiros n Kevin L. Pollpeter n Roger Cliff Dangerous Thresholds The RAND...impacts of U.S. policy in the current security envi- ronment: War and Escalation in South Asia, by John E . Peters, James Dickens, Derek Eaton, C...Striking First: Preemptive and Preventive Attack in U.S. National Security Policy, by Karl P. Muel- ler, Jasen J. Castillo, Forrest E . Morgan, Negeen

Treatment-related mortality in patients with advanced-stage hodgkin lymphoma: an analysis of the german hodgkin study group.

PubMed

Wongso, Diana; Fuchs, Michael; Plütschow, Annette; Klimm, Beate; Sasse, Stephanie; Hertenstein, Bernd; Maschmeyer, Georg; Vieler, Tom; Dührsen, Ulrich; Lindemann, Walter; Aulitzky, Walter; Diehl, Volker; Borchmann, Peter; Engert, Andreas

2013-08-01

The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated). In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15. Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%. The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.

Conflict escalation in paediatric services: findings from a qualitative study.

PubMed

Forbat, Liz; Teuten, Bea; Barclay, Sarah

2015-08-01

To explore clinician and family experiences of conflict in paediatric services, in order to map the trajectory of conflict escalation. Qualitative interview study, employing extreme-case sampling. Interviews were analysed using an iterative thematic approach to identify common themes regarding the experience and escalation of conflict. Thirty-eight health professionals and eight parents. All participants had direct experience of conflict, including physical assault and court proceedings, at the interface of acute and palliative care. Two teaching hospitals, one district general hospital and two paediatric hospices in England, in 2011. Conflicts escalate in a predictable manner. Clearly identifiable behaviours by both clinicians and parents are defined as mild, moderate and severe. Mild describes features like the insensitive use of language and a history of unresolved conflict. Moderate involves a deterioration of trust, and a breakdown of communication and relationships. Severe marks disintegration of working relationships, characterised by behavioural changes including aggression, and a shift in focus from the child's best interests to the conflict itself. Though conflicts may remain at one level, those which escalated tended to move sequentially from one level to the next. Understanding how conflicts escalate provides clinicians with a practical, evidence-based framework to identify the warning signs of conflict in paediatrics. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Avoiding escalation from play to aggression in adult male rats: The role of ultrasonic calls.

PubMed

Burke, Candace J; Kisko, Theresa M; Pellis, Sergio M; Euston, David R

2017-11-01

Play fighting is most commonly associated with juvenile animals, but in some species, including rats, it can continue into adulthood. Post-pubertal engagement in play fighting is often rougher and has an increased chance of escalation to aggression, making the use of play signals to regulate the encounter more critical. During play, both juvenile and adult rats emit many 50-kHz calls and some of these may function as play facilitating signals. In the present study, unfamiliar adult male rats were introduced in a neutral enclosure and their social interactions were recorded. While all pairs escalated their playful encounters to become rougher, only the pairs in which one member was devocalized escalated to serious biting. A Monte Carlo shuffling technique was used for the analysis of the correlations between the overt playful and aggressive actions performed and the types and frequencies of various 50-kHz calls that were emitted. The analysis revealed that lower frequency (20-30kHz) calls with a flat component maybe particularly critical for de-escalating encounters and so allowing play to continue. Moreover, coordinating calls reciprocally, with either the same call mimicked in close, temporal association or with complementary calls emitted by participants as they engage in complementary actions (e.g., attacking the nape, being attacked on the nape), appeared to be ways with which calls could be potentially used to avoid escalation to aggression and so sustain playful interactions. Copyright © 2017 Elsevier B.V. All rights reserved.

Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal

PubMed Central

Reed, Brian; Ho, Ann; Kreek, Mary Jeanne

2011-01-01

Rationale/objectives Although continued heroin use and relapse are thought to be motivated, in part, by the positive incentive-motivational value attributed to heroin, little is understood about heroin’s incentive value during the relapse-prone state of withdrawal. This study uses place preference to measure the incentive value attributed to escalating-dose heroin in the context of heroin dependence. Methods Male Fischer rats were exposed chronically to escalating doses of heroin in the homecage and during place preference conditioning sessions. Conditioned preference for the context paired with escalating-dose heroin was tested after homecage exposure was discontinued and rats entered acute spontaneous withdrawal. Individuals’ behavioral and locomotor responses to heroin and somatic withdrawal signs were recorded. Results Conditioned preference for the heroin-paired context was strong in rats that received chronic homecage exposure to escalating-dose heroin and were tested in acute withdrawal. Behavioral responses to heroin (e.g., stereotypy) varied widely across individuals, with rats that expressed stronger heroin preference also expressing stronger behavioral activation in response to heroin. Individual differences in preference were also related to locomotor responses to heroin but not to overt somatic withdrawal signs. Conclusions Escalating doses of heroin evoked place preference in rats, suggesting that positive incentive-motivational value is attributed to this clinically relevant pattern of drug exposure. This study offers an improved preclinical model for studying dependence and withdrawal and provides insight into individual vulnerabilities to addiction-like behavior. PMID:21748254

Escalator: An Autonomous Scheduling Scheme for Convergecast in TSCH

PubMed Central

Oh, Sukho; Hwang, DongYeop; Kim, Ki-Hyung; Kim, Kangseok

2018-01-01

Time Slotted Channel Hopping (TSCH) is widely used in the industrial wireless sensor networks due to its high reliability and energy efficiency. Various timeslot and channel scheduling schemes have been proposed for achieving high reliability and energy efficiency for TSCH networks. Recently proposed autonomous scheduling schemes provide flexible timeslot scheduling based on the routing topology, but do not take into account the network traffic and packet forwarding delays. In this paper, we propose an autonomous scheduling scheme for convergecast in TSCH networks with RPL as a routing protocol, named Escalator. Escalator generates a consecutive timeslot schedule along the packet forwarding path to minimize the packet transmission delay. The schedule is generated autonomously by utilizing only the local routing topology information without any additional signaling with other nodes. The generated schedule is guaranteed to be conflict-free, in that all nodes in the network could transmit packets to the sink in every slotframe cycle. We implement Escalator and evaluate its performance with existing autonomous scheduling schemes through a testbed and simulation. Experimental results show that the proposed Escalator has lower end-to-end delay and higher packet delivery ratio compared to the existing schemes regardless of the network topology. PMID:29659508

Escalation of drug self-administration as a hallmark of persistent addiction liability

PubMed Central

Edwards, Scott; Koob, George F.

2013-01-01

Drug addiction is a progressive, relapsing disease comprised of interlocking stages of disordered motivation. Numerous animal models describing various stages of the addiction process have been developed over the past few decades, providing considerable advantages for the modeling of drug addiction compared with other complex psychiatric disease states. Escalation of drug self-administration has emerged as a widely accepted operant conditioning model of excessive drug intake. We further argue here that drug-escalated animals represent a comprehensive model of addiction according to the manifestations of behavioral neuroadaptations resulting directly or indirectly from excessive drug consumption. In particular, drug-escalated animals exhibit a host of symptoms in line with multiple Diagnostic and Statistical Manual of Mental Disorders criteria for substance dependence, which can be summarized as an emergence of uncontrollable drug-taking and drug-seeking behaviors as a consequence of within-circuit and between-circuit neuroadaptations. Such a transition from impulsive drug sampling to compulsive intake represents a highly valid conceptualization of the addiction timeline in humans, and further investigation of persistent or near-permanent (e.g. epigenetic) neuroadaptations generated by operant drug intake escalation models will continue to provide mechanisms and therapeutic interventions for reversing the aberrant neuroplasticity underlying addiction. PMID:23839030

The development of an inherent safety approach to the prevention of domino accidents.

PubMed

Cozzani, Valerio; Tugnoli, Alessandro; Salzano, Ernesto

2009-11-01

The severity of industrial accidents in which a domino effect takes place is well known in the chemical and process industry. The application of an inherent safety approach for the prevention of escalation events leading to domino accidents was explored in the present study. Reference primary scenarios were analyzed and escalation vectors were defined. Inherent safety distances were defined and proposed as a metric to express the intensity of the escalation vectors. Simple rules of thumb were presented for a preliminary screening of these distances. Swift reference indices for layout screening with respect to escalation hazard were also defined. Two case studies derived from existing layouts of oil refineries were selected to understand the potentialities coming from the application in the methodology. The results evidenced that the approach allows a first comparative assessment of the actual domino hazard in a layout, and the identification of critical primary units with respect to escalation events. The methodology developed also represents a useful screening tool to identify were to dedicate major efforts in the design of add-on measures, optimizing conventional passive and active measures for the prevention of severe domino accidents.

Dose escalation methods in phase I cancer clinical trials.

PubMed

Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

2009-05-20

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

Tobacco use harm reduction, elimination, and escalation in a large military cohort.

PubMed

Klesges, Robert C; Sherrill-Mittleman, Deborah; Ebbert, Jon O; Talcott, G Wayne; Debon, Margaret

2010-12-01

We evaluated changing patterns of tobacco use following a period of forced tobacco abstinence in a US military cohort to determine rates of harm elimination (e.g., tobacco cessation), harm reduction (e.g., from smoking to smokeless tobacco use), and harm escalation (e.g., from smoking to dual use or from smokeless tobacco use to smoking or dual use). Participants were 5225 Air Force airmen assigned to the health education control condition in a smoking cessation and prevention trial. Tobacco use was assessed by self-report at baseline and 12 months. Among 114 baseline smokers initiating smokeless tobacco use after basic military training, most demonstrated harm escalation (87%), which was 5.4 times more likely to occur than was harm reduction (e.g., smoking to smokeless tobacco use). Harm reduction was predicted, in part, by higher family income and belief that switching from cigarettes to smokeless tobacco is beneficial to health. Harm escalation predictors included younger age, alcohol use, longer smoking history, and risk-taking. When considering a harm reduction strategy with smokeless tobacco, the tobacco control community should balance anticipated benefits of harm reduction with the risk of harm escalation and the potential for adversely affecting public health.

Escalator: An Autonomous Scheduling Scheme for Convergecast in TSCH.

PubMed

Oh, Sukho; Hwang, DongYeop; Kim, Ki-Hyung; Kim, Kangseok

2018-04-16

Time Slotted Channel Hopping (TSCH) is widely used in the industrial wireless sensor networks due to its high reliability and energy efficiency. Various timeslot and channel scheduling schemes have been proposed for achieving high reliability and energy efficiency for TSCH networks. Recently proposed autonomous scheduling schemes provide flexible timeslot scheduling based on the routing topology, but do not take into account the network traffic and packet forwarding delays. In this paper, we propose an autonomous scheduling scheme for convergecast in TSCH networks with RPL as a routing protocol, named Escalator. Escalator generates a consecutive timeslot schedule along the packet forwarding path to minimize the packet transmission delay. The schedule is generated autonomously by utilizing only the local routing topology information without any additional signaling with other nodes. The generated schedule is guaranteed to be conflict-free, in that all nodes in the network could transmit packets to the sink in every slotframe cycle. We implement Escalator and evaluate its performance with existing autonomous scheduling schemes through a testbed and simulation. Experimental results show that the proposed Escalator has lower end-to-end delay and higher packet delivery ratio compared to the existing schemes regardless of the network topology.

20. BANKING ROOM, LOOKING SOUTH FROM NORTHWEST CORNER, SHOWING ESCALATOR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

20. BANKING ROOM, LOOKING SOUTH FROM NORTHWEST CORNER, SHOWING ESCALATOR ENTRANCE FROM STREET ON RIGHT AND BALCONY EDGES OF TWO MEZZANINES BEYOND - Philadelphia Saving Fund Society, Twelfth & Market Streets, Philadelphia, Philadelphia County, PA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, P; Kuo, L; Yorke, E

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after themore » full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach. MSKCC has a research agreement with Varian Medical System.« less

Observational evidence that urbanisation and neighbourhood deprivation are associated with escalation in chronic pharmacological pain treatment: a longitudinal population-based study in the Netherlands

PubMed Central

Buijs, Servaas; Strik, Jacqueline; Lousberg, Richel; Smit, Jasper; van Kleef, Maarten; van Os, Jim

2012-01-01

Objective To examine, in the light of the association between urban environment and poor mental health, whether urbanisation and neighbourhood deprivation are associated with analgesic escalation in chronic pharmacological pain treatment and whether escalation is associated with prescriptions of psychotropic medication. Design Longitudinal analysis of a population-based routine dispensing database in the Netherlands. Setting Representative sample of pharmacies, covering 73% of the Dutch nationwide medication consumption in the primary care and hospital outpatient settings. Participants 449 410 patients aged 15–85 years were included, of whom 166 374 were in the Starter group and 283 036 in the Continuation group of chronic analgesic treatment. Main outcome measure Escalation of analgesics (ie, change to a higher level of analgesic potency, classified across five levels) in association with urbanisation (five levels) and dichotomous neighbourhood deprivation was analysed over a 6-month observation period. Methods Ordered logistic multivariate model evaluating analgesic treatment. Results In both Starter and Continuation groups, escalation was positively associated with urbanisation in a dose–response fashion (Starter group: OR (urbanisation level 1 compared with level 5): 1.24, 95% CI 1.18 to 1.30; Continuation group: OR 1.18, 95% CI 1.14 to 1.23). An additional association was apparent with neighbourhood deprivation (Starter group: OR 1.07, 95% CI 1.02 to 1.11; Continuation group: OR 1.04, 95% CI 1.01 to 1.08). Use of somatic and particularly psychotropic co-medication was associated with escalation in both groups. Conclusions Escalation of chronic analgesic treatment is associated with urban and deprived environments and occurs in a context of adding psychotropic medication prescriptions. These findings suggest that pain outcomes and mental health outcomes share factors that increase risk and remedy suffering. PMID:22815464

Attachment and Jealousy: Understanding the Dynamic Experience of Jealousy Using the Response Escalation Paradigm.

PubMed

Huelsnitz, Chloe O; Farrell, Allison K; Simpson, Jeffry A; Griskevicius, Vladas; Szepsenwol, Ohad

2018-04-01

Jealousy is a complex, dynamic experience that unfolds over time in relationship-threatening situations. Prior research has used retrospective reports that cannot disentangle initial levels and change in jealousy in response to escalating threat. In three studies, we examined responses to the Response Escalation Paradigm (REP)-a 5-stage hypothetical scenario in which individuals are exposed to increasing levels of relationship threat-as a function of attachment orientations. Highly anxious individuals exhibited hypervigilant, slow escalation response patterns, interfered earlier in the REP, felt more jealousy, sadness, and worry when they interfered, and wanted to engage in more vigilant, destructive, and passive behaviors aimed at their partner. Highly avoidant individuals felt more anger when they interfered in the REP and wanted to engage in more partner-focused, destructive behaviors. The REP offers a dynamic method for inducing and examining jealousy and introduces a novel approach to studying other emotional experiences.

Maternal depression and trait anger as risk factors for escalated physical discipline.

PubMed

Shay, Nicole L; Knutson, John F

2008-02-01

To test the hypothesized anger-mediated relation between maternal depression and escalation of physical discipline, 122 economically disadvantaged mothers were assessed for current and lifetime diagnoses of depression using the Current Depressive Episode, Past Depression, and Dysthymia sections of the Structured Clinical Interview for DSM-IV (SCID) and a measure of current depressive symptoms, the Beck Depression Inventory-Second Edition (BDI-II). Escalation of physical discipline was assessed using a video analog parenting task; maternal anger not specific to discipline was assessed using the Spielberger Trait Anger Expression Inventory. Reports of anger were associated with the diagnosis of depression and depressive symptoms. Bootstrap analyses of indirect effects indicated that the link between depression and escalated discipline was mediated by anger. Parallel analyses based on BDI-II scores identified a marginally significant indirect effect of depression on discipline. Findings suggest that anger and irritability are central to the putative link between depression and harsh discipline.

Promoting de-escalation of commitment: a regulatory-focus perspective on sunk costs.

PubMed

Molden, Daniel C; Hui, Chin Ming

2011-01-01

People frequently escalate their commitment to failing endeavors. Explanations for such behavior typically involve loss aversion, failure to recognize other alternatives, and concerns with justifying prior actions; all of these factors produce recommitment to previous decisions with the goal of erasing losses and vindicating these decisions. Solutions to escalation of commitment have therefore focused on external oversight and divided responsibility during decision making to attenuate loss aversion, blindness to alternatives, and justification biases. However, these solutions require substantial resources and have additional adverse effects. The present studies tested an alternative method for de-escalating commitment: activating broad motivations for growth and advancement (promotion). This approach should reduce concerns with loss and increase perceptions of alternatives, thereby attenuating justification motives. In two studies featuring hypothetical financial decisions, activating promotion motivations reduced recommitment to poorly performing investments as compared with both not activating any additional motivations and activating motivations for safety and security (prevention).

Evolutionary aspects of anxiety disorders.

PubMed

Price, John S

2003-09-01

DANGER AND HARM ARE AVOIDED BY STRATEGIC DECISIONS MADE AT ALL THREE LEVELS OF THE TRIUNE FOREBRAIN: rational (neomammalian), emotional (paleomammalian), and instinctive (reptilian). This applies also to potential harm from conspecifics, which leads to a choice between escalating and de-escalating strategies. Anxiety is a component of de-escalating strategies mediated by the paleomammalian and reptilian forebrains. When the neomammalian (rational) brain fails to deal with the threat of conspecific danger, these more primitive de-escalating strategies may be activated and may present as anxiety disorders. The capacity for concealment of anxiety and other forms of negative affect has also evolved, and excessive concealment may lead to psychopaihology by breaking the negative feedback loop of excessive motivation, leading to impaired performance, leading to signals of distress, and leading to reduced exhortation to succeed on the part of parents and teachers; this situation is illustrated by a model based on the Yerkes-Dodson law.

Evolutionary aspects of anxiety disorders

PubMed Central

Price, John S.

2003-01-01

Danger and harm are avoided by strategic decisions made at all three levels of the triune forebrain: rational (neomammalian), emotional (paleomammalian), and instinctive (reptilian). This applies also to potential harm from conspecifics, which leads to a choice between escalating and de-escalating strategies. Anxiety is a component of de-escalating strategies mediated by the paleomammalian and reptilian forebrains. When the neomammalian (rational) brain fails to deal with the threat of conspecific danger, these more primitive de-escalating strategies may be activated and may present as anxiety disorders. The capacity for concealment of anxiety and other forms of negative affect has also evolved, and excessive concealment may lead to psychopaihology by breaking the negative feedback loop of excessive motivation, leading to impaired performance, leading to signals of distress, and leading to reduced exhortation to succeed on the part of parents and teachers; this situation is illustrated by a model based on the Yerkes-Dodson law. PMID:22033473

Preventing and De-escalating Aggressive Behavior Among Adult Psychiatric Patients: A Systematic Review of the Evidence.

PubMed

Gaynes, Bradley N; Brown, Carrie L; Lux, Linda J; Brownley, Kimberly A; Van Dorn, Richard A; Edlund, Mark J; Coker-Schwimmer, Emmanuel; Weber, Rachel Palmieri; Sheitman, Brian; Zarzar, Theodore; Viswanathan, Meera; Lohr, Kathleen N

2017-08-01

The project goal was to compare the effectiveness of strategies to prevent and de-escalate aggressive behaviors among psychiatric patients in acute care settings, including interventions for reducing use of seclusion and restraint. Relevant databases were systematically reviewed for comparative studies of violence prevention and de-escalation strategies involving adult psychiatric patients in acute care settings. Studies (trials and cohort studies) were required to report on aggression or seclusion or restraint outcomes. Both risk of bias, an indicator of quality of individual studies, and strength of evidence (SOE) for each outcome were independently assessed by two study personnel. Seventeen primary studies met inclusion criteria. Evidence was limited for benefits and harms; information about characteristics that might modify the interventions' effectiveness, such as race or ethnicity, was especially limited. All but one study had a medium or high risk of bias and thus presented worrisome limitations. For prevention, risk assessment reduced both aggression and use of seclusion and restraint (low SOE), and multimodal interventions reduced the use of seclusion and restraint (low SOE). SOE for all other interventions, whether aimed at preventing or de-escalating aggression, and for modifying characteristics was insufficient. Available evidence about strategies for preventing and de-escalating aggressive behavior among psychiatric patients is very limited. Two preventive strategies, risk assessment and multimodal interventions consistent with the Six Core Strategies principles, may effectively lower aggressive behavior and use of seclusion and restraint, but more research is needed on how best to prevent and de-escalate aggressive behavior in acute care settings.

Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?

PubMed

Hudson, Andrew; Chan, Clara; Woolf, David; McWilliam, Alan; Hiley, Crispin; O'Connor, James; Bayman, Neil; Blackhall, Fiona; Faivre-Finn, Corinne

2018-04-01

The current standard of care for the management of inoperable stage 3 non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (cCRT) using radiotherapy dose-fractionation and chemotherapy regimens that were established 3 decades ago. In an attempt to improve the chances of long-term control from cCRT, dose-escalation of the radiotherapy dose was assessed in the RTOG 0617 randomised control study comparing the standard 60 Gy in 30 fractions with a high-dose arm receiving 74 Gy in 37 fractions. Following the publication of this trial the thoracic oncology community were surprised to learn that there was worse survival in the dose-escalated arm and that for now the standard of care must remain with the lower dose. In this article we review the RTOG 0617 paper with subsequent analyses and studies to explore why the use of dose-escalated cCRT in stage 3 NSCLC has not shown the benefits that were expected. The overarching theme of this opinion piece is how heterogeneity between stage 3 NSCLC cases in terms of patient, tumour, and clinical factors may obscure the potential benefits of dose-escalation by causing imbalances in the arms of studies such as RTOG 0617. We also examine recent advances in the staging, management, and technological delivery of radiotherapy in NSCLC and how these may be employed to optimise cCRT trials in the future and ensure that any potential benefits of dose-escalation can be detected. Copyright © 2018 Elsevier B.V. All rights reserved.

Behavioral characterization of escalated aggression induced by GABAB receptor activation in the dorsal raphé nucleus

PubMed Central

Takahashi, Aki; Schilit, Arielle N.; Kim, Jisoo; DeBold, Joseph F.; Koide, Tsuyoshi; Miczek, Klaus A.

2013-01-01

Rationale Pharmacological activation of GABAB receptors in the dorsal raphé nucleus (DRN) can escalate territorial aggression in male mice. Objectives We characterized this escalated aggression in terms of its behavioral and environmental determinants. Methods Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN ten minutes before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment. Results Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts. Conclusions For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat. PMID:22395428

Suicide Attempts in a Longitudinal Sample of Adolescents Followed Through Adulthood: Evidence of Escalation

PubMed Central

Goldston, David B.; Daniel, Stephanie S.; Erkanli, Alaattin; Heilbron, Nicole; Doyle, Otima; Weller, Bridget; Sapyta, Jeffrey

2015-01-01

Objectives This study was designed to examine escalation in repeat suicide attempts from adolescence through adulthood, as predicted by sensitization models (and reflected in increasing intent and lethality with repeat attempts, decreasing amount of time between attempts, and decreasing stress to trigger attempts) Method In a prospective study of 180 adolescents followed through adulthood after a psychiatric hospitalization, suicide attempts and antecedent life events were repeatedly assessed (M = 12.6 assessments, SD = 5.1) over an average of 13 years, 6 months (SD = 4 years, 5 months). Multivariate logistic, multiple linear, and negative binomial regression models were used to examine patterns over time. Results After age 17-18, the majority of suicide attempts were repeat attempts (i.e., made by individuals with prior suicidal behavior). Intent increased both with increasing age, and with number of prior attempts. Medical lethality increased as a function of age but not recurrent attempts. The time between successive suicide attempts decreased as a function of number of attempts. The amount of precipitating life stress was not related to attempts. Conclusions Adolescents and young adults show evidence of escalation of recurrent suicidal behavior, with increasing suicidal intent and decreasing time between successive attempts. However, evidence that sensitization processes account for this escalation was inconclusive. Effective prevention programs that reduce the likelihood of individuals attempting suicide for the first time (and entering this cycle of escalation), and relapse prevention interventions that interrupt the cycle of escalating suicidal behavior among individuals who already have made attempts are critically needed. PMID:25622200

Organizational Conflict Management as Disputing Process: The Problem of Social Escalation.

ERIC Educational Resources Information Center

Morrill, Calvin; Thomas, Cheryl King

1992-01-01

Develops an instrument to study organizational conflict management as a disputing process involving the social escalation from grievance to conflict and dispute stages. Finds differences in dispute process according to different strengths of informal relations. (SR)

School District Health Care Expense: Moderating the Escalation Rate.

ERIC Educational Resources Information Center

Abel, Gene P.

1991-01-01

The cafeteria plan for health insurance benefits employers by reducing the overall escalation of health costs. Employees benefit by tailoring their benefit packages to their needs to including the option to decline coverage because of spouse employment. (MLF)

Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias

ClinicalTrials.gov

2018-02-13

Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia

Use of PET and Other Functional Imaging to Guide Target Delineation in Radiation Oncology.

PubMed

Verma, Vivek; Choi, J Isabelle; Sawant, Amit; Gullapalli, Rao P; Chen, Wengen; Alavi, Abass; Simone, Charles B

2018-06-01

Molecular and functional imaging is increasingly being used to guide radiotherapy (RT) management and target delineation. This review summarizes existing data in several disease sites of various functional imaging modalities, chiefly positron emission tomography/computed tomography (PET/CT), with respect to RT target definition and management. For gliomas, differentiation between postoperative changes and viable tumor is discussed, as well as focal dose escalation and reirradiation. Head and neck neoplasms may also benefit from precise PET/CT-based target delineation, especially for cancers of unknown primary; focal dose escalation is also described. In lung cancer, PET/CT can influence coverage of tumor volumes, dose escalation, and adaptive management. For cervical cancer, PET/CT as an adjunct to magnetic resonance imaging planning is discussed, as are dose escalation and delineation of avoidance targets such as the bone marrow. The emerging role of choline-based PET for prostate cancer and its impact on dose escalation is also described. Lastly, given the essential role of PET/CT for target definition in lymphoma, phase III trials of PET-directed management are reviewed, along with novel imaging modalities. Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic care going forward. Copyright © 2018 Elsevier Inc. All rights reserved.

Lack of Benefit for the Addition of Androgen Deprivation Therapy to Dose-Escalated Radiotherapy in the Treatment of Intermediate- and High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauss, Daniel, E-mail: dkrauss@beaumont.edu; Kestin, Larry; Ye, Hong

2011-07-15

Purpose: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). Methods and Materials: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA {>=}20, or Stage T3. Patients were additionally divided specifically by Gleason score, presencemore » of palpable disease, and PSA level to further define subgroups benefitting from ADT. Results: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason {>=}8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. Conclusion: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.« less

Vital signs and other observations used to detect deterioration in pregnant women: an analysis of vital sign charts in consultant-led UK maternity units.

PubMed

Smith, G B; Isaacs, R; Andrews, L; Wee, M Y K; van Teijlingen, E; Bick, D E; Hundley, V

2017-05-01

Obstetric early warning systems are recommended for monitoring hospitalised pregnant and postnatal women. We decided to compare: (i) vital sign values used to define physiological normality; (ii) symptoms and signs used to escalate care; (iii) type of chart used; and (iv) presence of explicit instructions for escalating care. One-hundred-and-twenty obstetric early warning charts and escalation protocols were obtained from consultant-led maternity units in the UK and Channel Islands. These data were extracted: values used to determine normality for each maternal vital sign; chart colour-coding; instructions following early warning system triggering; other criteria used as triggers. There was considerable variation in the charts, warning systems and escalation protocols. Of 120 charts, 89.2% used colour; 69.2% used colour-coded escalation systems. Forty-one (34.2%) systems required the calculation of weighted scores. Seventy-five discrete combinations of 'normal' vital sign ranges were found, the most common being: heart rate=50-99beats/min; respiratory rate=11-20breaths/min; blood pressure, systolic=100-149mmHg, diastolic ≤89mmHg; SpO 2 =95-100%; temperature=36.0-37.9°C; and Alert-Voice-Pain-Unresponsive assessment=Alert. Most charts (90.8%) provided instructions about who to contact following triggering, but only 41.7% gave instructions about subsequent observation frequency. The wide range of 'normal' vital sign values in different systems suggests a lack of equity in the processes for detecting deterioration and escalating care in hospitalised pregnant and postnatal women. Agreement regarding 'normal' vital sign ranges is urgently required and would assist the development of a standardised obstetric early warning system and chart. Copyright © 2017 Elsevier Ltd. All rights reserved.

Gradual escalation of use-of-force reduces police officer injury.

PubMed

Jetelina, Katelyn K; Reingle Gonzalez, Jennifer M; Bishopp, Stephen A

2018-02-01

To examine how escalation through the force continuum predicts officer injury in the presence of citizen aggression, while controlling for extraneous factors, like citizen and officer characteristics. Cross-sectional data were extracted from 2244 use-of-force reports from the Dallas Police Department in 2015. Multilevel, mixed logistic regression models were used to evaluate the relationship between use of force and officer injury. Multilevel path analysis tested indirect and direct relationships between citizen aggression and officer injury. Results suggest that gradual escalation through the force continuum significantly decreases officer injury when a citizen is actively aggressive (β=-1.06, p value <0.001). Further, non-Hispanic black officers (β=-0.22, p value <0.001) and Hispanic officers (β=-0.08, p value <0.05) are less likely to gradually escalate through the force continuum, due to lower odds of verbal commands (black: OR=0.51, 95% CI 0.39 to 0.68; Hispanic: OR=0.77, 95% CI 0.60 to 0.99) and hard-empty hand control (black: OR=0.58, 95% CI 0.43 to 0.77) compared with white officers. Finally, officers with higher tenure (β=-0.01, p value <0.001) are less likely to gradually escalate through the force continuum. Escalation through the force continuum significantly reduces police officer injury. Future research should assess whether further environmental or situational factors contribute to the strong relationship between use of force and officer injury. Also, reliability and validity testing of use-of-force reports is an imperative direction for future research. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Radiobiological evaluation of simultaneously dose-escalated versus non-escalated intensity-modulated radiation therapy for patients with upper thoracic esophageal cancer.

PubMed

Huang, Bao-Tian; Wu, Li-Li; Guo, Long-Jia; Xu, Liang-Yu; Huang, Rui-Hong; Lin, Pei-Xian; Chen, Jian-Zhou; Li, De-Rui; Chen, Chuang-Zhen

2017-01-01

To compare the radiobiological response between simultaneously dose-escalated and non-escalated intensity-modulated radiation therapy (DE-IMRT and NE-IMRT) for patients with upper thoracic esophageal cancer (UTEC) using radiobiological evaluation. Computed tomography simulation data sets for 25 patients pathologically diagnosed with primary UTEC were used in this study. DE-IMRT plan with an escalated dose of 64.8 Gy/28 fractions to the gross tumor volume (GTV) and involved lymph nodes from 25 patients pathologically diagnosed with primary UTEC, was compared to an NE-IMRT plan of 50.4 Gy/28 fractions. Dose-volume metrics, tumor control probability (TCP), and normal tissue complication probability for the lung and spinal cord were compared. In addition, the risk of acute esophageal toxicity (AET) and late esophageal toxicity (LET) were also analyzed. Compared with NE-IMRT plan, we found the DE-IMRT plan resulted in a 14.6 Gy dose escalation to the GTV. The tumor control was predicted to increase by 31.8%, 39.1%, and 40.9% for three independent TCP models. The predicted incidence of radiation pneumonitis was similar (3.9% versus 3.6%), and the estimated risk of radiation-induced spinal cord injury was extremely low (<0.13%) in both groups. Regarding the esophageal toxicities, the estimated grade ≥2 and grade ≥3 AET predicted by the Kwint model were increased by 2.5% and 3.8%. Grade ≥2 AET predicted using the Wijsman model was increased by 14.9%. The predicted incidence of LET was low (<0.51%) in both groups. Radiobiological evaluation reveals that the DE-IMRT dosing strategy is feasible for patients with UTEC, with significant gains in tumor control and minor or clinically acceptable increases in radiation-induced toxicities.

MEOSAR Cost Escalation Risk

DTIC Science & Technology

2014-02-25

CMA, of Directorate of Costing Services, (D Cost S), requested DRDC CORA’s assistance with determining the cost escalation risk for the Medium Earth...Orbit Search and Rescue (MEOSAR) project. Following a project meeting on 12 February 2014, Mr. Iburg provided us with subject matter expert(s) (SME) cost

78 FR 32294 - Escalate Capital Partners SBIC I, L.P., License No. 06/06-0335; Notice Seeking Exemption Under...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

..., L.P. proposes to provide loan financing to SailPoint Technologies, Inc., 6034 West Courtyard Drive... Associate of Escalate Capital Partners, SBIC I, L.P., owns more than ten percent of SailPoint Technologies...

29 CFR 1917.116 - Elevators and escalators.

Code of Federal Regulations, 2010 CFR

2010-07-01

... or more floors of a structure. The term excludes such devices as conveyors, tiering or piling... devices shall not be overridden or made inoperable. (e) Elevators and escalators shall be thoroughly... shall be conducted by designated persons. Records of the results of the latest annual elevator...

Older adult falls at a metropolitan airport: 2009-2010.

PubMed

Howland, Jonathan; Bibi, Salma; English, James; Dyer, Sophia; Peterson, Elizabeth W

2012-04-01

We investigated falls at a metropolitan airport to determine fall incidence, identify potential causes of these falls, and suggest opportunities for mitigation. We used deidentified incident reports of all falls requiring EMS response that occurred at the airport during 2009 and 2010. On average, one fall occurred every 2.3days. Ninety-six percent (96%) of falls occurred in terminals. Of all falls, 44% occurred on escalators, making escalators the most common location. Seventy-two percent (72%) of fallers were females; 43% were ≥65years; 92% of all falls resulted in a documented injury; 37% of falls resulted in transport to hospital emergency departments. Escalator fall risks include carrying bags (due to changes in baggage fees), using cells phones, not using handrails, and compromised strength and balance. Diverting at-risk passengers to elevators could significantly reduce the overall falls. Interventions targeting escalator falls have the greatest promise for reducing falls at this airport. Copyright © 2012 National Safety Council and Elsevier Ltd. All rights reserved.

Maternal Depression and Trait Anger as Risk Factors for Escalated Physical Discipline

PubMed Central

Shay, Nicole L.; Knutson, John F.

2008-01-01

To test the hypothesized anger-mediated relation between maternal depression and escalation of physical discipline, 122 economically disadvantaged mothers were assessed for current and lifetime diagnoses of depression using the Current Depressive Episode, Past Depression, and Dysthymia sections of the Structured Clinical Interview for DSM-IV (SCID) and a measure of current depressive symptoms, the Beck Depression Inventory–Second Edition (BDI-II). Escalation of physical discipline was assessed using a video analog parenting task; maternal anger not specific to discipline was assessed using the Spielberger Trait Anger Expression Inventory. Reports of anger were associated with the diagnosis of depression and depressive symptoms. Bootstrap analyses of indirect effects indicated that the link between depression and escalated discipline was mediated by anger. Parallel analyses based on BDI-II scores identified a marginally significant indirect effect of depression on discipline. Findings suggest that anger and irritability are central to the putative link between depression and harsh discipline. PMID:18174347

The effects of mortality salience on escalation of commitment.

PubMed

Yen, Chih-Long; Lin, Chun-Yu

2012-01-01

Based on propositions derived from terror management theory (TMT), the current study proposes that people who are reminded of their mortality exhibit a higher degree of self-justification behavior to maintain their self-esteem. For this reason, they could be expected to stick with their previous decisions and invest an increasing amount of resources in those decisions, despite the fact that negative feedback has clearly indicated that they might be on a course toward failure (i.e., "escalation of commitment"). Our experiment showed that people who were reminded of their mortality were more likely to escalate their level of commitment by maintaining their current course of action. Two imaginary scenarios were tested. One of the scenarios involved deciding whether to send additional troops into the battlefield when previous attempts had failed; the other involved deciding whether to continue developing an anti-radar fighter plane when the enemy had already developed a device to detect it. The results supported our hypothesis that mortality salience increases the tendency to escalate one's level of commitment.

A Unified Electronic Tool for CPR and Emergency Treatment Escalation Plans Improves Communication and Early Collaborative Decision Making for Acute Hospital Admissions.

PubMed

Johnson, Mae; Whyte, Martin; Loveridge, Robert; Yorke, Richard; Naleem, Shairana

2017-01-01

The National Confidential Enquiry into Patient Outcomes and Death (NCEPOD) report 'Time to Intervene' (2012) stated that in a substantial number of cases, resuscitation is attempted when it was thought a 'do not attempt cardiopulmonary resuscitation' (DNACPR) decision should have been in place. Early decisions about CPR status and advance planning about limits of care now form part of national recommendations by the UK Resuscitation Council (2016). Treatment escalation plans (TEP) document what level of treatment intervention would be appropriate if a patient were to become acutely unwell and were not previously formally in place at King's College Hospital. A unifying paper based form was successfully piloted in the Acute Medical Unit, introducing the TEP and bringing together decision making around both treatment escalation and CPR status. Subsequently an electronic order-set for CPR status and treatment escalation was launched in April 2015 which led to a highly visible CPR and escalation status banner on the main screen at the top of the patient's electronic record. Ultimately due to further iterations in the electronic process by December 2016, all escalation decisions for acutely admitted patients now have high quality supporting, explanatory documentation with 100% having TEPs in place. There is now widespread multidisciplinary engagement in the process of defining limits of care for acutely admitted medical patients within the first 14 hours of admission and a strategy for rolling this process out across all the divisions of the hospital through our Deteriorating Patient Group (DPG). The collaborative design with acute medical, palliative and intensive care teams and the high visibility provided by the electronic process in the Electronic Patient Record (EPR) has enhanced communication with these teams, patients, nursing staff and the multidisciplinary team by ensuring clarity through a universally understood process about escalation and CPR. Clarity and openness about these discussions have been welcomed by patient focus groups facilitated via our acute medicine patient experience committee. There has been a shift in medical culture where transparency about limits of care has contributed to improving patient safety and quality of care through reducing unnecessary CPR supported by focus groups of staff.

14 CFR 1214.803 - Reimbursement policy.

Code of Federal Regulations, 2012 CFR

2012-01-01

... operations will be developed after NASA has obtained more operational experience. (b) Escalation. Payments shall be escalated in accordance with the Shuttle policy. (c) Customers shall reimburse NASA an amount... reimburse NASA for standard Spacelab services an amount which is a pro rata share of: (i) The appropriate...

14 CFR 1214.803 - Reimbursement policy.

Code of Federal Regulations, 2013 CFR

2013-01-01

... operations will be developed after NASA has obtained more operational experience. (b) Escalation. Payments shall be escalated in accordance with the Shuttle policy. (c) Customers shall reimburse NASA an amount... reimburse NASA for standard Spacelab services an amount which is a pro rata share of: (i) The appropriate...

14 CFR § 1214.803 - Reimbursement policy.

Code of Federal Regulations, 2014 CFR

2014-01-01

... operations will be developed after NASA has obtained more operational experience. (b) Escalation. Payments shall be escalated in accordance with the Shuttle policy. (c) Customers shall reimburse NASA an amount... reimburse NASA for standard Spacelab services an amount which is a pro rata share of: (i) The appropriate...

14 CFR 1214.803 - Reimbursement policy.

Code of Federal Regulations, 2011 CFR

2011-01-01

... operations will be developed after NASA has obtained more operational experience. (b) Escalation. Payments shall be escalated in accordance with the Shuttle policy. (c) Customers shall reimburse NASA an amount... reimburse NASA for standard Spacelab services an amount which is a pro rata share of: (i) The appropriate...

Escalating Commitment to a Relationship: The Sexual Harassment Trap.

ERIC Educational Resources Information Center

Williams, Karen B.; Cyr, Ramona R.

1992-01-01

Studies divergent sexual harassment perceptions in a case of a perpetrator's gradual sexual advancements and a target's escalating commitment to their relationship, using 60 male and 60 female undergraduates. Males' ratings of sexual harassment decreased when female target participated in increasingly informal friendly interactions. Females'…

Neonatal Early Warning Tools for recognising and responding to clinical deterioration in neonates cared for in the maternity setting: A retrospective case-control study.

PubMed

Paliwoda, Michelle; New, Karen; Bogossian, Fiona

2016-09-01

All newborns are at risk of deterioration as a result of failing to make the transition to extra uterine life. Signs of deterioration can be subtle and easily missed. It has been postulated that the use of an Early Warning Tool may assist clinicians in recognising and responding to signs of deterioration earlier in neonates, thereby preventing a serious adverse event. To examine whether observations from a Standard Observation Tool, applied to three neonatal Early Warning Tools, would hypothetically trigger an escalation of care more frequently than actual escalation of care using the Standard Observation Tool. A retrospective case-control study. A maternity unit in a tertiary public hospital in Australia. Neonates born in 2013 of greater than or equal to 34(+0) weeks gestation, admitted directly to the maternity ward from their birthing location and whose subsequent deterioration required admission to the neonatal unit, were identified as cases from databases of the study hospital. Each case was matched with three controls, inborn during the same period and who did not experience deterioration and neonatal unit admission. Clinical and physiological data recorded on a Standard Observation Tool, from time of admission to the maternity ward, for cases and controls were charted onto each of three Early Warning Tools. The primary outcome was whether the tool 'triggered an escalation of care'. Descriptive statistics (n, %, Mean and SD) were employed. Cases (n=26) comprised late preterm, early term and post-term neonates and matched by gestational age group with 3 controls (n=78). Overall, the Standard Observation Tool triggered an escalation of care for 92.3% of cases compared to the Early Warning Tools; New South Wales Health 80.8%, United Kingdom Newborn Early Warning Chart 57.7% and The Australian Capital Territory Neonatal Early Warning Score 11.5%. Subgroup analysis by gestational age found differences between the tools in hypothetically triggering an escalation of care. The Standard Observation Tool triggered an escalation of care more frequently than the Early Warning Tools, which may be as a result of behavioural data captured on the Standard Observation Tool and escalated, which could not be on the Early Warning Tools. Findings demonstrate that a single tool applied to all gestational age ranges may not be effective in identifying early deterioration or may over trigger an escalation of care. Further research is required into the sensitivity and specificity of Early Warning Tools in neonatal sub-populations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy.

PubMed

Tran, Ly-Binh-An; Bol, Anne; Labar, Daniel; Karroum, Oussama; Bol, Vanesa; Jordan, Bénédicte; Grégoire, Vincent; Gallez, Bernard

2014-11-01

Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions. Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas. For 9L-gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen. (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F-FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non-responsive to carbogen. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Direct Observations of Parenting and Real-time Negative Affect among Adolescent Smokers and Non-Smokers

PubMed Central

Richmond, Melanie J.; Mermelstein, Robin J.; Wakschlag, Lauren S.

2012-01-01

Objective This longitudinal study examined how observations of parental general communication style and control with their adolescents predicted changes in negative affect over time for adolescent smokers and non-smokers. Method Participants were 9th and 10th grade adolescents (N = 111; 56.8% female) who had all experimented with cigarettes and were thus at risk for continued smoking and escalation; 36% of these adolescents (n = 40) had smoked in the past month at baseline and were considered smokers in the present analyses. Adolescents participated separately with mothers and fathers in observed parent-adolescent problem-solving discussions to assess parenting at baseline. Adolescent negative affect was assessed at baseline, 6- and 24-months via ecological momentary assessment. Results Among both smoking and non-smoking adolescents, escalating negative affect significantly increased risk for future smoking. Higher quality maternal and paternal communication predicted a decline in negative affect over 1.5 years for adolescent smokers but was not related to negative affect for non-smokers. Controlling maternal, but not paternal, parenting predicted escalation in negative affect for all adolescents. Conclusions Findings suggest that reducing negative affect among experimenting youth can reduce risk for smoking escalation. Therefore, family-based prevention efforts for adolescent smoking escalation might consider parental general communication style and control as intervention targets. However, adolescent smoking status and parent gender may moderate these effects. PMID:23153193

Direct observations of parenting and real-time negative affect among adolescent smokers and nonsmokers.

PubMed

Richmond, Melanie J; Mermelstein, Robin J; Wakschlag, Lauren S

2013-01-01

This longitudinal study examined how observations of parental general communication style and control with their adolescents predicted changes in negative affect over time for adolescent smokers and nonsmokers. Participants were 9th- and 10th-grade adolescents (N = 111; 56.8% female) who had all experimented with cigarettes and were thus at risk for continued smoking and escalation; 36% of these adolescents (n = 40) had smoked in the past month at baseline and were considered smokers in the present analyses. Adolescents participated separately with mothers and fathers in observed parent-adolescent problem-solving discussions to assess parenting at baseline. Adolescent negative affect was assessed at baseline, 6 months, and 24 months via ecological momentary assessment. Among both smoking and nonsmoking adolescents, escalating negative affect significantly increased risk for future smoking. Higher quality maternal and paternal communication predicted a decline in negative affect over 1.5 years for adolescent smokers but was not related to negative affect for nonsmokers. Controlling maternal, but not paternal, parenting predicted escalation in negative affect for all adolescents. Findings suggest that reducing negative affect among experimenting youth can reduce risk for smoking escalation. Therefore, family-based prevention efforts for adolescent smoking escalation might consider parental general communication style and control as intervention targets. However, adolescent smoking status and parent gender may moderate these effects.

Symptom Induction and De-escalation in the Treatment of Panic Attacks.

ERIC Educational Resources Information Center

Dattilio, Frank M.

1990-01-01

Describes technique known as symptom induction and de-escalation for panic attacks in which goal is to reproduce the type of situation that may precipitate an attack and then to show the client how the attacks can be "turned on" as well as "turned off." (ABL)

Indicators, Predictors, and Determinants of Conflict Escalation and De-escalation. A Review of the Psychological Literature

DTIC Science & Technology

2009-05-01

des outils habituels de la psychologie parce que ces gens ne sont pratiquement jamais disponibles pour les chercheurs. Pour compenser, des méthodes...Ballard, E. J. (1983). Canadian prime ministers: Complexity in political crises. Canadian Psychology/ Psychologie Canadienne, 24, 125-129. Beasley

Bloc Concentration and Dispute Escalation among the Major Powers, 1830-1965.

ERIC Educational Resources Information Center

Stoll, Richard J.

1984-01-01

In the 1830-1914 era, when the major powers had a high level of political-military interdependence and alliance flexibility, changes in bloc concentration were a good predictor of dispute escalation. But bloc concentration had little predictive ability when this interdependence and alliance flexibility declined (1919-1965). (RM)

18 CFR Table 1 to Part 301 - Functionalization and Escalation Codes

Code of Federal Regulations, 2010 CFR

2010-04-01

... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Functionalization and Escalation Codes 1 Table 1 to Part 301 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS FOR FEDERAL POWER MARKETING ADMINISTRATIONS AVERAGE SYSTEM COST...

18 CFR Table 1 to Part 301 - Functionalization and Escalation Codes

Code of Federal Regulations, 2012 CFR

2012-04-01

... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Functionalization and Escalation Codes 1 Table 1 to Part 301 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS FOR FEDERAL POWER MARKETING ADMINISTRATIONS AVERAGE SYSTEM COST...

18 CFR Table 1 to Part 301 - Functionalization and Escalation Codes

Code of Federal Regulations, 2013 CFR

2013-04-01

... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Functionalization and Escalation Codes 1 Table 1 to Part 301 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS FOR FEDERAL POWER MARKETING ADMINISTRATIONS AVERAGE SYSTEM COST...

18 CFR Table 1 to Part 301 - Functionalization and Escalation Codes

Code of Federal Regulations, 2014 CFR

2014-04-01

... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Functionalization and Escalation Codes 1 Table 1 to Part 301 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS FOR FEDERAL POWER MARKETING ADMINISTRATIONS AVERAGE SYSTEM COST...

18 CFR Table 1 to Part 301 - Functionalization and Escalation Codes

Code of Federal Regulations, 2011 CFR

2011-04-01

... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Functionalization and Escalation Codes 1 Table 1 to Part 301 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS FOR FEDERAL POWER MARKETING ADMINISTRATIONS AVERAGE SYSTEM COST...

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

PubMed

El-Khoueiry, Anthony B; Sangro, Bruno; Yau, Thomas; Crocenzi, Todd S; Kudo, Masatoshi; Hsu, Chiun; Kim, Tae-You; Choo, Su-Pin; Trojan, Jörg; Welling, Theodore H; Meyer, Tim; Kang, Yoon-Koo; Yeo, Winnie; Chopra, Akhil; Anderson, Jeffrey; Dela Cruz, Christine; Lang, Lixin; Neely, Jaclyn; Tang, Hao; Dastani, Homa B; Melero, Ignacio

2017-06-24

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Escalating and Descending Schedules of Incentives on Cigarette Smoking in Smokers without Plans to Quit

ERIC Educational Resources Information Center

Romanowich, Paul; Lamb, R. J.

2010-01-01

Contingent incentives can reduce substance abuse. Escalating payment schedules, which begin with a small incentive magnitude and progressively increase with meeting the contingency, increase smoking abstinence. Likewise, descending payment schedules can increase cocaine abstinence. The current experiment enrolled smokers without plans to quit in…

Sensemaking in Enterprise Resource Planning Project Deescalation: An Empirical Study

ERIC Educational Resources Information Center

Battleson, Douglas Aloys

2013-01-01

Enterprise resource planning (ERP) projects, a type of complex information technology project, are very challenging and expensive to implement. Past research recognizes that escalation, defined as the commitment to a failing course of action, is common in such projects. While the factors that contribute to escalation (e.g., project conditions,…

18 CFR 301.4 - Exchange Period Average System Cost determination.

Code of Federal Regulations, 2010 CFR

2010-04-01

... paragraph (a)(3)(iv) of this section indicates that no escalation to the Account will be made. (5... the Exchange Period by the same rate of growth as total Contract System Load. (7) If any of the escalators specified in paragraph (a) of this section are no longer available, Bonneville will designate a...

18 CFR 301.4 - Exchange Period Average System Cost determination.

Code of Federal Regulations, 2011 CFR

2011-04-01

... paragraph (a)(3)(iv) of this section indicates that no escalation to the Account will be made. (5... the Exchange Period by the same rate of growth as total Contract System Load. (7) If any of the escalators specified in paragraph (a) of this section are no longer available, Bonneville will designate a...

18 CFR 301.4 - Exchange Period Average System Cost determination.

Code of Federal Regulations, 2013 CFR

2013-04-01

... paragraph (a)(3)(iv) of this section indicates that no escalation to the Account will be made. (5... the Exchange Period by the same rate of growth as total Contract System Load. (7) If any of the escalators specified in paragraph (a) of this section are no longer available, Bonneville will designate a...

18 CFR 301.4 - Exchange Period Average System Cost determination.

Code of Federal Regulations, 2012 CFR

2012-04-01

... paragraph (a)(3)(iv) of this section indicates that no escalation to the Account will be made. (5... the Exchange Period by the same rate of growth as total Contract System Load. (7) If any of the escalators specified in paragraph (a) of this section are no longer available, Bonneville will designate a...

18 CFR 301.4 - Exchange Period Average System Cost determination.

Code of Federal Regulations, 2014 CFR

2014-04-01

... paragraph (a)(3)(iv) of this section indicates that no escalation to the Account will be made. (5... the Exchange Period by the same rate of growth as total Contract System Load. (7) If any of the escalators specified in paragraph (a) of this section are no longer available, Bonneville will designate a...

The Escalating Costs of Higher Education.

ERIC Educational Resources Information Center

Kirshstein, Rita J.; And Others

This congressionally mandated study of the escalating cost of higher education focuses on: (1) identifying the cost of obtaining a higher education and determining how that cost has changed from 1976-77 to 1987-88; (2) determining specific causes of such cost changes; (3) forecasting the future cost of obtaining a higher education; (4) evaluating…

Temporal Aspects of Moral Disengagement in School Bullying: Crystallization or Escalation?

ERIC Educational Resources Information Center

Obermann, Marie-Louise

2013-01-01

This study investigated the stability and change in bullying behavior and their relation to increases and decreases in moral disengagement, specifically exploring whether crystallization and escalation of disengagement occur. Within a 1-year span, two sets of data were collected. A total of 567 sixth to eighth graders participated in both data…

Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

ClinicalTrials.gov

2016-02-18

Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

Factorial structure and convergent and discriminant validity of the E (Empathy) scale.

PubMed

Tran, Ulrich S; Laireiter, Anton-Rupert; Schmitt, David P; Neuner, Christine; Leibetseder, Max; Szente-Voracek, Sara Leyla; Voracek, Martin

2013-10-01

The Empathy (E) scale has been proposed as a theoretically and psychometrically more satisfying alternative to existing self-report measures of empathy. Its four scales (facets) cover both components (cognitive vs. emotional) and both reality statuses (fictitious vs. real-life) of empathy in pairwise combinations. Confirmatory factor analyses of the E-scale in an Austrian community sample (N = 794) suggested that one prior assumption, namely the mutual orthogonality of these facets, may partly need revision; particularly, the E-scale facets seemed to reflect more strongly differences in the reality statuses than in the components of empathy. Utilizing numerous informative psychological traits, the scale's convergent and discriminant validity were examined. E-scale scores were consistently predicted by sex-related and relationship-related constructs and measures of antisocial attitudes and behavior. Among the Big Five personality dimensions, openness emerged as a major positive correlate of empathy. Sex and age were demographic correlates of E-scale scores (higher in women and the younger). Findings were discussed with regards to the definition and measurement of empathy.

Alcohol and violence: neuropeptidergic modulation of monoamine systems

PubMed Central

Miczek, Klaus A.; DeBold, Joseph F.; Hwa, Lara S.; Newman, Emily L.; de Almeida, Rosa M. M.

2015-01-01

Neurobiological processes underlying the epidemiologically-established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals that are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma-aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin-releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. Intermittent episodes of brief social defeat during aggressive confrontations are sufficient to cause long-lasting neuroadaptations that can lead to the escalation of alcohol consumption. PMID:26285061

Strategy escalation: an emerging paradigm for safe clinical development of T cell gene therapies.

PubMed

Junghans, Richard Paul

2010-06-10

Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs) for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications.

The utility of fecal calprotectin in predicting the need for escalation of therapy in inflammatory bowel disease.

PubMed

Kwapisz, Lukasz; Gregor, Jamie; Chande, Nilesh; Yan, Brian; Ponich, Terry; Mosli, Mahmoud

2017-08-01

Fecal calprotectin is an important biomarker used in the evaluation of inflammatory bowel disease. It has proven to be an effective tool in initial screening as well monitoring response to therapy. The aim of this study is to examine the utility of fecal calprotectin both as a predictor for the escalation of therapy in established inflammatory bowel disease and as a predictor of de novo diagnosis. Patients with signs and symptoms concerning for inflammatory bowel disease presenting to outpatient clinics were recruited to provide fecal calprotectin stool samples prior to endoscopic evaluation. Patients were followed up for at least one year and monitored clinically for any change in symptomatology, escalation of therapy or development of IBD, confirmed endoscopically. A total of 126 patients, of whom 72 were known to have underlying inflammatory bowel disease, were included in the final analysis. Among the patients with elevated fecal calprotectin levels and known inflammatory bowel disease, 66% (33/50) went on to have escalation of therapy within 12 months compared to 18% (4/22) if the fecal calprotectin levels were in the normal range (p < .0001). For the remaining patients who at baseline did not have inflammatory bowel disease and a normal endoscopic evaluation, elevated fecal calprotectin resulted in no cases (0/17) of a new diagnosis in the next 12 months. Fecal calprotectin is a useful test for predicting escalation of therapy in established inflammatory bowel disease.

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

Treating locally advanced lung cancer with a 1.5T MR-Linac - Effects of the magnetic field and irradiation geometry on conventionally fractionated and isotoxic dose-escalated radiotherapy.

PubMed

Bainbridge, Hannah E; Menten, Martin J; Fast, Martin F; Nill, Simeon; Oelfke, Uwe; McDonald, Fiona

2017-11-01

This study investigates the feasibility and potential benefits of radiotherapy with a 1.5T MR-Linac for locally advanced non-small cell lung cancer (LA NSCLC) patients. Ten patients with LA NSCLC were retrospectively re-planned six times: three treatment plans were created according to a protocol for conventionally fractionated radiotherapy and three treatment plans following guidelines for isotoxic target dose escalation. In each case, two plans were designed for the MR-Linac, either with standard (∼7mm) or reduced (∼3mm) planning target volume (PTV) margins, while one conventional linac plan was created with standard margins. Treatment plan quality was evaluated using dose-volume metrics or by quantifying dose escalation potential. All generated treatment plans fulfilled their respective planning constraints. For conventionally fractionated treatments, MR-Linac plans with standard margins had slightly increased skin dose when compared to conventional linac plans. Using reduced margins alleviated this issue and decreased exposure of several other organs-at-risk (OAR). Reduced margins also enabled increased isotoxic target dose escalation. It is feasible to generate treatment plans for LA NSCLC patients on a 1.5T MR-Linac. Margin reduction, facilitated by an envisioned MRI-guided workflow, enables increased OAR sparing and isotoxic target dose escalation for the respective treatment approaches. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease.

PubMed

Dubinsky, Marla C; Rosh, Joel; Faubion, William A; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M; Lazar, Andreas; Thakkar, Roopal B

2016-04-01

The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.

Student nurses' de-escalation of patient aggression: a pretest-posttest intervention study.

PubMed

Nau, Johannes; Halfens, Ruud; Needham, Ian; Dassen, Theo

2010-06-01

Experts recommend staff training to prevent and manage aggressive situations involving patients or their relatives. However, in many countries this subject is not covered in pre-registration nursing education. In addition, the evidence regarding its impact on practical placements remains weak. This study examines the influence of an aggression management training programme for nursing students on their performance in de-escalating aggressive patients. Pretest-posttest within-and-between-groups design. A School of Nursing in Germany. Convenience sample out of six classes of nursing students at differing educational levels (10th to 28th month of nursing education, n=78, mean age=22). In a cross-sectional and longitudinal two groups before and after design nursing students encountered two scenarios (A or B) with simulation patients. After completing the training, each student was confronted with the unknown other scenario. De-escalation experts from three German-speaking countries evaluated 156 video scenes using the De-escalating Aggressive Behaviour Scale (DABS), not knowing whether the videos had been recorded before or after the training. Mean values and statistical significance tests were computed to compare the results. The performance levels of students who had been trained rose significantly from 2.74 to 3.65 as measured by the DABS on a 5-point Likert scale (Wilcoxon test p<.001). The trained students managed scenario A significantly better than the untrained students (untrained 2.50, trained 3.70; Mann-Whitney-U-test p<.001,). Similar results were found for scenario B (untrained 3.01, trained 3.61; Mann-Whitney-U-test p<.001). No significant differences were found in the pretest results irrespective the students' age or duration of previous nursing education. Aggression management training is able to improve nursing students' performance in de-escalating aggressive behaviour. A maturation-effect on the de-escalating performance due to general nursing education or age is unlikely. (c) 2009 Elsevier Ltd. All rights reserved.

Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: Effects on striatal dopamine and opioid systems in C57BL/6J mice

PubMed Central

Zhang, Yong; Schlussman, Stefan D.; Rabkin, Jacqui; Butelman, Eduardo R.; Ho, Ann; Kreek, Mary Jeanne

2013-01-01

Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an “addiction-like cycle” in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal /13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal /14-day cocaine). Escalating-dose binge cocaine (15-30 mg/kg/injection x 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In “re-exposure” groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin (Pdyn), dopamine D1 (Drd1) and D2 (Drd2) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states. PMID:23164614

Impact of antibiotic de-escalation on clinical outcomes in community-acquired pneumococcal pneumonia.

PubMed

Viasus, Diego; Simonetti, Antonella F; Garcia-Vidal, Carolina; Niubó, Jordi; Dorca, Jordi; Carratalà, Jordi

2017-02-01

Although antibiotic de-escalation is regarded as a measure that reduces selection pressure, adverse drug effects and costs, evidence supporting this practice in community-acquired pneumococcal pneumonia (CAPP) is lacking. We carried out a retrospective analysis of prospectively collected data of a cohort of hospitalized adults with CAPP. Pneumococcal aetiology was established in patients with one or more positive cultures for Streptococcus pneumoniae obtained from blood, sterile fluids or sputum, and/or a positive urinary antigen test. De-escalation therapy was considered when the initial antibiotic therapy was narrowed to penicillin, amoxicillin or amoxicillin/clavulanate within the first 72 h after admission. The primary outcomes were 30 day mortality and length of hospital stay (LOS). Adjustment for confounders was performed with multivariate and propensity score analyses. Of 1410 episodes of CAPP, antibiotic de-escalation within the first 72 h after admission was performed in 166 cases. After adjustment, antibiotic de-escalation was not associated with a higher risk of mortality (OR = 0.83, 95% CI = 0.24-2.81), but it was found to be a protective factor for prolonged LOS (above the median) (OR = 0.46, 95% CI = 0.30-0.70). Similar results were found in patients classified into high-risk pneumonia severity index classes (IV-V), those with clinical instability and those with bacteraemia. No significant differences were documented in adverse drug reactions or readmission (<30 days). Antibiotic de-escalation seems to be safe and effective in reducing the duration of LOS, and did not adversely affect outcomes of patients with CAPP, even those with bacteraemia and severe disease, and those who were clinically unstable. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Riding the Escalator: How Dangerous is it Really?

PubMed Central

Schminke, Louisa H.; Jeger, Victor; Evangelopoulos, Dimitrios S.; Zimmerman, Heinz; Exadaktylos, Aristomenis K.

2013-01-01

Introduction: About 10,000 escalator-related injuries per year result in emergency department treatment in the United States. Since the 1990s, a steady increase has been reported, but few statistics on escalator-related injuries have been published worldwide. We have therefore analyzed escalator accident statistics in admissions to our hospital in Switzerland since 2000. Methods: Using retrospective electronic patient chart analysis, we included in our study patients >16 years treated over an 11-year period. We categorized patients in terms of gender, age and associated risk factors, and classified accidents according to day, time, location and cause. Resulting trauma was categorized according to type and location. We divided post-admission treatment into surgical and conservative, and into treatment as an outpatient, in a short-stay unit, or as a hospital admission. Women and men were compared using Fisher’s exact test. Results: We identified 173 patients with 285 discrete injuries. Of these, 87 patients (50%) were women. Fifty-three (61%) of the women and 38 (44%) of the men were >60 years old (P = 0.033). Fifty percent of the men (43/86) of the men, but only 7% (6/87) of the women showed signs of alcohol intoxication (P < 0.0001). Accidents in women occurred predominantly on Tuesdays (19/87; 22%) between 12pm and 6pm (35/87; 40%), and in men on Saturdays (16/86; 19%) between 6pm and 12am (29/86; 34%; P = 0.0097). Sixty-two percent (44/71) of the accidents were in public transport facilities and 30% (21/71) in shopping centers. The majority of injuries in women were to the lower extremities (49/87; 56%), while most accidents in men were to the head and neck (51/86; 59%; P = 0.0052). About half (90; 52%) of the patients were treated conservatively. Almost half of all patients (76, 44%) required hospital admission. Of those, 45% left the hospital within 24 hours of admission (short stay unit) and 55% stayed longer than 24 hours. Conclusion: Escalator accidents can result in severe trauma. Significant gender differences in escalator accidents have been observed. Alcohol intoxication and age are significant risk factors in escalator-related accidents and might be possible targets for preventive measures. PMID:23599850

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brower, Jeffrey V.; Chen, Shuai; Bassetti, Michael F.

Purpose: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Methods and Materials: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. Results: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received dosesmore » >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). Conclusions: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.« less

An introduction to the Emergency Department Adult Clinical Escalation protocol: ED-ACE.

PubMed

Coughlan, Eoin; Geary, Una; Wakai, Abel; O'Sullivan, Ronan; Browne, John; McAuliffe, Eilish; Ward, Marie; McDaid, Fiona; Deasy, Conor

2017-09-01

This study demonstrates how a participatory action research approach was used to address the challenge of the early and effective detection of the deteriorating patient in the ED setting. The approach enabled a systematic approach to patient monitoring and escalation of care to be developed to address the wide-ranging spectrum of undifferentiated presentations and the phases of ED care from triage to patient admission. This paper presents a longitudinal patient monitoring system, which aims to provide monitoring and escalation of care, where necessary, of adult patients from triage to admission to hospital in a manner that is feasible in the unique ED environment. An action research approach was taken to designing a longitudinal patient monitoring system appropriate for the ED. While the first draft protocol for post-triage monitoring and escalation was designed by a core research group, six clinical sites were included in iterative cycles of planning, action, reviewing and further planning. Reasons for refining the system at each site were collated and the protocol was adjusted accordingly before commencing the process at the next site. The ED Adult Clinical Escalation longitudinal patient monitoring system (ED-ACE) evolved through iterative cycles of design and testing to include: (1) a monitoring chart for adult patients; (2) a standardised approach to the monitoring and reassessment of patients after triage until they are assessed by a clinician; (3) the ISBAR (I=Identify, S=Situation, B=Background, A=Assessment, R=Recommendation) tool for interprofessional communication relating to clinical escalation; (4) a template for prescribing a patient-specific monitoring plan to be used by treating clinicians to guide patient monitoring from the time the patient is assessed until when they leave the ED and (5) a protocol for clinical escalation prompted by single physiological triggers and clinical concern. This tool offers a link in the 'Chain of Prevention' between the Manchester Triage System and ward-based early warning scores taking account of the importance of standardisation, while being sufficiently adaptable for the unique working environment and patient population in the ED. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012.

PubMed

Brower, Jeffrey V; Chen, Shuai; Bassetti, Michael F; Yu, Menggang; Harari, Paul M; Ritter, Mark A; Baschnagel, Andrew M

2016-12-01

To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

NASA Astrophysics Data System (ADS)

Bass, Christopher Paul

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

High-flow nasal prong oxygen therapy or nasopharyngeal continuous positive airway pressure for children with moderate-to-severe respiratory distress?*.

PubMed

ten Brink, Fia; Duke, Trevor; Evans, Janine

2013-09-01

The aim of this study was to compare the use of high-flow nasal prong oxygen therapy to nasopharyngeal continuous positive airway pressure in a PICU at a tertiary hospital; to understand the safety and effectiveness of high-flow nasal prong therapy; in particular, what proportion of children require escalation of therapy, whether any bedside monitoring data predict stability or need for escalation, and complications of the therapies. This was a prospective observational study of the first 6 months after the introduction of high-flow nasal prong oxygen therapy at the Royal Children's Hospital in Melbourne. Data were collected on all children who were managed with either high-flow nasal prong oxygen therapy or nasopharyngeal continuous positive airway pressure. The mode of respiratory support was determined by the treating medical staff. Data were collected on each patient before the use of high-flow nasal prong or nasopharyngeal continuous positive airway pressure, at 2 hours after starting the therapy, and the children were monitored and data collected until discharge from the ICU. Therapy was considered to be escalated if children on high-flow nasal prong required a more invasive form or higher level of respiratory support, including nasopharyngeal continuous positive airway pressure or mask bilevel positive airway pressure or endotracheal intubation and mechanical ventilation. Therapy was considered to be escalated if children on nasopharyngeal continuous positive airway pressure required bilevel positive airway pressure or intubation and mechanical ventilation. As the first mode of respiratory support, 72 children received high-flow nasal prong therapy and 37 received nasopharyngeal continuous positive airway pressure. Forty-four patients (61%) who received high-flow nasal prong first were weaned to low-flow oxygen or to room air and 21 (29%) required escalation of respiratory support, compared with children on nasopharyngeal continuous positive airway pressure: 21 (57%) weaned successfully and 9 (24%) required escalation. Repeated treatment and crossover were common in this cohort. Throughout the study duration, escalation to a higher level of respiratory support was needed in 26 of 100 high-flow nasal prong treatment episodes (26%) and in 10 of 55 continuous positive airway pressure episodes (18%; p = 0.27). The need for escalation could be predicted by two of failure of normalization of heart rate and respiratory rate, and if the FIO2 did not fall to lower than 0.5, 2 hours after starting high-flow nasal prong therapy. Nasopharyngeal continuous positive airway pressure was required for significantly longer periods than high-flow nasal prong (median 48 and 18 hours, respectively; p ≤ 0.001). High-flow nasal prong therapy is a safe form of respiratory support for children with moderate-to-severe respiratory distress, across a large range of diagnoses, whose increased work of breathing or hypoxemia is not relieved by standard oxygen therapy. About one quarter of all children will require escalation to another form of respiratory support. This can be predicted by simple bedside observations.

Subthreshold Conditions as Precursors for Full Syndrome Disorders: A 15-Year Longitudinal Study of Multiple Diagnostic Classes

ERIC Educational Resources Information Center

Shankman, Stewart A.; Lewinsohn, Peter M.; Klein, Daniel N.; Small, Jason W.; Seeley, John R.; Altman, Sarah E.

2009-01-01

Background: There has been increasing interest in the distinction between subthreshold and full syndrome disorders and specifically whether subthreshold conditions escalate or predict the onset of full syndrome disorders over time. Most of these studies, however, examined whether a single subthreshold condition escalates into the full syndrome…

Some Take the Glass Escalator, Some Hit the Glass Ceiling? Career Consequences of Occupational Sex Segregation.

ERIC Educational Resources Information Center

Hultin, Mia

2003-01-01

Analysis of Swedish longitudinal data (1,535 men, 1,584 women) showed that men in female-dominated occupations have substantially better internal promotion opportunities than equally qualified women. In male-dominated occupations, men and women have equal internal promotion chances. Results suggest a "glass escalator" advantage for men…

An Evaluation of Three Methods of Saying "No" to Avoid an Escalating Response Class Hierarchy

ERIC Educational Resources Information Center

Mace, F. Charles; Pratt, Jamie L.; Prager, Kevin L.; Pritchard, Duncan

2011-01-01

We evaluated the effects of three different methods of denying access to requested high-preference activities on escalating problem behavior. Functional analysis and response class hierarchy (RCH) assessment results indicated that 4 topographies of problem behaviors displayed by a 13-year-old boy with high-functioning autism constituted an RCH…

Ascent into Darkness: Escalating Negativity in the Administration of Schools in the Kirov Region, 1931-1941

ERIC Educational Resources Information Center

Holmes, Larry E.

2006-01-01

Reporting within the administration responsible for primary and secondary schools in the Kirov region from the early 1930s to 1941 followed a script of escalating negativity in which the higher the chain of command, the more negative the assessment. School directors wrote positive quarterly and annual evaluations. District and municipal…

Response Acquisition and Fixed-Ratio Escalation Based on Interresponse Times in Rats

ERIC Educational Resources Information Center

Taylor, Tracy G.; Galuska, Chad M.; Banna, Kelly; Yahyavi-Firouz-Abadi, Noushin; See, Ronald E.

2010-01-01

The effectiveness of a fixed-ratio (FR) escalation procedure, developed by Pinkston and Branch (2004) and based on interresponse times (IRTs), was assessed during lever-press acquisition. Forty-nine experimentally naive adult male Long Evans rats were deprived of food for 24 hr prior to an extended acquisition session. Before the start of the…

Preventing and De-Escalating Ethical Conflict: A Communication-Training Mediation Model.

PubMed

Levin, Tomer T; Parker, Patricia A

2015-01-01

While ethical conflicts in the provision of healthcare are common, the current third-party mediator model is limited by a lack of expert ethical mediators, who are often not on site when conflict escalates. In order to improve clinical outcomes in situations such as conflicts at the end of life, we suggest that clinicians-physicians, nurses and social workers-be trained to prevent and de-escalate emerging conflicts. This can be achieved using a mediation model framed by a communication-training approach. A case example is presented and the model is discussed. The implication of this preventative/early intervention model for improving clinical outcomes, in particular end-of life conflict, is considered. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Requirements of a new communication technology for handover and the escalation of patient care: a multi-stakeholder analysis.

PubMed

Johnston, Maximilian J; King, Dominic; Arora, Sonal; Cooper, Kerri; Panda, Neha Aparajita; Gosling, Rebecca; Singh, Kaushiki; Sanders, Bradley; Cox, Benita; Darzi, Ara

2014-08-01

In order to enable safe and efficient information transfer between health care professionals during clinical handover and escalation of care, existing communication technologies must be updated. This study aimed to provide a user-informed guide for the development of an application-based communication system (ABCS), tailored for use in patient handover and escalation of care. Current methods of inter-professional communication in health care along with information system needs for communication technology were identified through literature review. A focus group study was then conducted according to a topic guide developed by health innovation and safety researchers. Fifteen doctors and 11 nurses from three London hospitals participated in a mixture of homogeneous and heterogeneous sessions. The sessions were recorded and transcribed verbatim before being subjected to thematic analysis. Seventeen information system needs were identified from the literature review. Participants identified six themes detailing user perceptions of current communication technology, attitudes to smartphone technology and anticipated requirements of an application produced for handover and escalation of care. Participants were in favour of an ABCS over current methods and expressed enthusiasm for a system with integrated patient information and group-messaging functions. Despite concerns regarding confidentiality and information governance a robust guide for development and implementation of an ABCS was produced, taking input from multiple stakeholders into account. Handover and escalation of care are vital processes for patient safety and communication within these must be optimized. An ABCS for health care professionals would be a welcome innovation and may lead to improvements in patient safety. © 2014 John Wiley & Sons, Ltd.

The De-Escalating Aggressive Behaviour Scale: development and psychometric testing.

PubMed

Nau, Johannes; Halfens, Ruud; Needham, Ian; Dassen, Theo

2009-09-01

This paper is a report of a study to develop and test the psychometric properties of a scale measuring nursing students' performance in de-escalation of aggressive behaviour. Successful training should lead not merely to more knowledge and amended attitudes but also to improved performance. However, the quality of de-escalation performance is difficult to assess. Based on a qualitative investigation, seven topics pertaining to de-escalating behaviour were identified and the wording of items tested. The properties of the items and the scale were investigated quantitatively. A total of 1748 performance evaluations by students (rater group 1) from a skills laboratory were used to check distribution and conduct a factor analysis. Likewise, 456 completed evaluations by de-escalation experts (rater group 2) of videotaped performances at pre- and posttest were used to investigate internal consistency, interrater reliability, test-retest reliability, effect size and factor structure. Data were collected in 2007-2008 in German. Factor analysis showed a unidimensional 7-item scale with factor loadings ranging from 0.55 to 0.81 (rater group 1) and 0.48 to 0.88 (rater group 2). Cronbach's alphas of 0.87 and 0.88 indicated good internal consistency irrespective of rater group. A Pearson's r of 0.80 confirmed acceptable test-retest reliability, and interrater reliability Intraclass Correlation 3 ranging from 0.77 to 0.93 also showed acceptable results. The effect size r of 0.53 plus Cohen's d of 1.25 indicates the capacity of the scale to detect changes in performance. Further research is needed to test the English version of the scale and its validity.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

The social process of escalation: a promising focus for crisis management research

PubMed Central

2012-01-01

Background This study identifies a promising, new focus for the crisis management research in the health care domain. After reviewing the literature on health care crisis management, there seems to be a knowledge-gap regarding organisational change and adaption, especially when health care situations goes from normal, to non-normal, to pathological and further into a state of emergency or crisis. Discussion Based on studies of escalating situations in obstetric care it is suggested that two theoretical perspectives (contingency theory and the idea of failure as a result of incomplete interaction) tend to simplify the issue of escalation rather than attend to its complexities (including the various power relations among the stakeholders involved). However studying the process of escalation as inherently complex and social allows us to see the definition of a situation as normal or non-normal as an exercise of power in itself, rather than representing a putatively correct response to a particular emergency. Implications The concept of escalation, when treated this way, can help us further the analysis of clinical and institutional acts and competence. It can also turn our attention to some important elements in a class of social phenomenon, crises and emergencies, that so far have not received the attention they deserve. Focusing on organisational choreography, that interplay of potential factors such as power, professional identity, organisational accountability, and experience, is not only a promising focus for future naturalistic research but also for developing more pragmatic strategies that can enhance organisational coordination and response in complex events. PMID:22704075

Increasing the Effectiveness of De-escalation of Aggressive Behaviors in the Young Child.

ERIC Educational Resources Information Center

Mueller, Alison

Due to the overuse of physical containment within the agency where this practicum study was conducted, an in-service training program was designed and implemented aimed at better preparing staff to de-escalate aggressive behavior. A three hour training session and a conclusive one-and-a-half hour long testing period (involving lecture, role play,…

Learning to make collective decisions: the impact of confidence escalation.

PubMed

Mahmoodi, Ali; Bang, Dan; Ahmadabadi, Majid Nili; Bahrami, Bahador

2013-01-01

Little is known about how people learn to take into account others' opinions in joint decisions. To address this question, we combined computational and empirical approaches. Human dyads made individual and joint visual perceptual decision and rated their confidence in those decisions (data previously published). We trained a reinforcement (temporal difference) learning agent to get the participants' confidence level and learn to arrive at a dyadic decision by finding the policy that either maximized the accuracy of the model decisions or maximally conformed to the empirical dyadic decisions. When confidences were shared visually without verbal interaction, RL agents successfully captured social learning. When participants exchanged confidences visually and interacted verbally, no collective benefit was achieved and the model failed to predict the dyadic behaviour. Behaviourally, dyad members' confidence increased progressively and verbal interaction accelerated this escalation. The success of the model in drawing collective benefit from dyad members was inversely related to confidence escalation rate. The findings show an automated learning agent can, in principle, combine individual opinions and achieve collective benefit but the same agent cannot discount the escalation suggesting that one cognitive component of collective decision making in human may involve discounting of overconfidence arising from interactions.

Selection of the initial design for the two-stage continual reassessment method.

PubMed

Jia, Xiaoyu; Ivanova, Anastasia; Lee, Shing M

2017-01-01

In the two-stage continual reassessment method (CRM), model-based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. This is appealing to clinicians because it allows a sufficient number of patients to be assigned to each of the lower dose levels before escalating to higher dose levels. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose-escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifying cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose-finding study for which clinicians explicitly stated their desire to assign at least one patient to each of the lower dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided.

Seeking Middle Ground: Reconciling Political Appeal With Military Distaste For Gradual Escalation

DTIC Science & Technology

2001-05-01

such an environment , coercion plays an important role in international relations. As coercion and gradualism increase in appeal and likelihood...idealism. In such an environment , coercion plays an important role in international relations. As coercion and gradualism increase in appeal and...Seeking Middle Ground: Reconciling Political Appeal With Military Distaste For Gradual Escalation A Monograph by Major R. Christopher Stockton United

Justified Humanitarian Intervention: Operation ALLIED FORCE

DTIC Science & Technology

2013-04-25

muster the political will to intervene early and forcefully to prevent escalation, genocide , and spillover to neighboring states that will destroy...increased as the violence escalated. The memory of human rights atrocities in Bosnia, the recent failure by the UN to prevent genocide in Rwanda ...guidance which President Clinton developed during the 1994 genocide in Rwanda . In PDD-25 President Clinton identified “humanitarian disasters requiring

An Investigation of the Relationships between Goals and Software Project Escalation: Insights from Goal Setting and Goal Orientation Theories

ERIC Educational Resources Information Center

Lee, Jong Seok

2013-01-01

Escalation of commitment is manifested as a behavior in which an individual resists withdrawing from a failing course of action despite negative feedback, and it is an enduring problem that occurs in a variety of situations, including R&D investment decisions and software project overruns. To date, a variety of theoretical explanations have…

78 FR 32294 - Escalate Capital Partners SBIC I, L.P., License No. 06/06-0335; Notice Seeking Exemption Under...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

... Notice is hereby given that Escalate Capital Partners SBIC I, L.P., 300 W. 6th Street, Suite 2250, Austin... Renewable Energy, LLC, which is portfolio company of its Associate Austin Ventures. The financing is brought within the purview of Sec. 107.730(a)(l) of the Regulations because Austin Ventures, an Associate of...

Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rahimi, Asal, E-mail: asal.rahimi@utsouthwestern.edu; Thomas, Kimberly; Spangler, Ann

Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohortmore » to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting.« less

Intermittent Access to Ethanol Drinking Facilitates the Transition to Excessive Drinking After Chronic Intermittent Ethanol Vapor Exposure.

PubMed

Kimbrough, Adam; Kim, Sarah; Cole, Maury; Brennan, Molly; George, Olivier

2017-08-01

Alcohol binge drinking in humans is thought to increase the risk for alcohol use disorder (AUD). Unclear is whether drinking patterns (e.g., bingelike or stable drinking) differentially affect the transition to compulsive-like drinking in dependent individuals. We examined whether chronic bingelike drinking facilitates the transition to compulsive-like drinking in rats. Male Wistar rats were given 5 months of intermittent access to ethanol (EtOH) (IAE) or continuous access to EtOH (CAE) in a 2-bottle choice paradigm. Then, rats were given chronic intermittent EtOH (CIE) vapor exposure. Escalation of EtOH intake and compulsive-like responding for EtOH, using a progressive-ratio schedule of reinforcement and quinine-adulterated EtOH, were measured. IAE rats escalated EtOH drinking after 2 weeks of 2-bottle choice, whereas CAE rats exhibited stable EtOH drinking for 5 months. After 8 weeks of CIE, both IAE + CIE and CAE + CIE rats escalated their EtOH intake. However, IAE rats escalated their EtOH intake weeks sooner than CAE rats and exhibited greater EtOH intake. No differences in compulsive-like responding were found between IAE + CIE and CAE + CIE rats. However, both IAE + CIE and CAE + CIE rats showed strong compulsive-like responding compared with rats without prior IAE or CAE. Chronic EtOH drinking at stable or escalated levels for several months is associated with more compulsive-like responding for EtOH in rats that are exposed to CIE compared with rats without a prior history of EtOH drinking. Moreover, IAE facilitated the transition to compulsive-like responding for EtOH after CIE exposure, reflected by the escalation of EtOH intake. These results suggest that IAE may facilitate the transition to AUD. This study indicates that despite a moderate level of EtOH drinking, the IAE animal model is highly relevant to early stages of alcohol abuse and suggests that it may be associated with neuroadaptations that produce a faster transition to alcohol dependence. Copyright © 2017 by the Research Society on Alcoholism.

Efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: an open-label randomized controlled trial.

PubMed

Rattanaumpawan, Pinyo; Werarak, Peerawong; Jitmuang, Anupop; Kiratisin, Pattarachai; Thamlikitkul, Visanu

2017-03-01

Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria (GNB) infections. The study objectives were to evaluate efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae. We conducted a randomized controlled trial of adult patients with documented ESBL-producing Enterobacteriaceae infections who had received any group 2 carbapenem for less than 96 h. In the intervention group, the previously-prescribed group 2 carbapenem was de-escalated to ertapenem. In the control group, the group 2 carbapenem was continued. During June 2011-December 2014, 32 patients were randomized to the de-escalation group and 34 to the control group. Most common sites of infection were urinary tract infection (42%). Characteristics of both groups were comparable. By using a 15% predefined margin, ertapenem was non-inferior to control group regarding the clinical cure rate (%Δ = 14.0 [95% confidence interval: -2.4 to 31.1]), the microbiological eradication rate (%Δ = 4.1 [-5.0 to 13.4]), and the superimposed infection rate (%Δ = -16.5 [-38.4 to 5.3]). Patients in the de-escalation group had a significantly lower 28-day mortality rate (9.4% vs. 29.4%; P = .05), a significantly shorter median length of stay (16.5 days [4.0-73.25] vs. 20.0 days [1.0-112.25]; P = .04), and a significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P = .05). Ertapenem could be safely used as de-escalation therapy for ESBL-producing Enterobacteriaceae infections, once the susceptibility profiles are known. Future studies are needed to investigate ertapenem efficacy against ESBL-producing Enterobacteriaceae pneumonia to determine its applicability in life-threatening conditions. ClinicalTrials.gov identifier: NCT01297842 . Registered on 14 February 2011. First patient enrolled on 27 June 2011.

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PubMed

Socinski, Mark A; Morris, David E; Halle, Jan S; Moore, Dominic T; Hensing, Thomas A; Limentani, Steven A; Fraser, Robert; Tynan, Maureen; Mears, Andrea; Rivera, M Patricia; Detterbeck, Frank C; Rosenman, Julian G

2004-11-01

Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism.

PubMed

Newman, Emily L; Albrechet-Souza, Lucas; Andrew, Peter M; Auld, John G; Burk, Kelly C; Hwa, Lara S; Zhang, Eric Y; DeBold, Joseph F; Miczek, Klaus A

2018-06-01

Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake. We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking. Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4 weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride. Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17-30 mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100 mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100 mg/kg) or metyrapone (50 mg/kg), all mice reduced their EtOH intake while increasing their water consumption. Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors.

Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management.

PubMed

Coburn, Brian W; Bendlin, Kayli A; Sayles, Harlan; Meza, Jane; Russell, Cynthia L; Mikuls, Ted R

2017-09-01

Patient and provider factors, including allopurinol medication adherence, affect gout treatment outcomes. The aim of this study was to examine associations of patient and provider factors with optimal gout management. Linking longitudinal health and pharmacy dispensing records to questionnaire data, we assessed patient and provider factors among 612 patients with gout receiving allopurinol during a recent 1-year period. Associations of patient (medication adherence and patient activation) and provider factors (dose escalation, low-dose initiation, and anti-inflammatory prophylaxis) with serum urate (SU) goal achievement of less than 6.0 mg/dL were examined using multivariable logistic regression. Medication adherence was assessed as a mediator of these factors with goal achievement. A majority of patients (63%) were adherent, whereas a minority received dose escalation (31%). Medication adherence was associated with initiation of daily allopurinol doses of 100 mg/d or less (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.20-2.76). In adjusted models, adherence (OR, 2.35; 95% CI, 1.50-3.68) and dose escalation (OR, 2.48; 95% CI, 2.48-4.25) were strongly associated with SU goal attainment. Low starting allopurinol dose was positively associated with SU goal attainment (OR, 1.11; 95% CI, 1.02-1.20) indirectly through early adherence, but also had a negative direct association with SU goal attainment (OR, 0.21; 95% CI, 0.12-0.37). Medication adherence and low starting dose combined with dose escalation represent promising targets for future gout quality improvement efforts. Low starting dose is associated with better SU goal attainment through increased medication adherence, but may be beneficial only in settings where appropriate dose escalation is implemented.

Therapeutic Drug Monitoring Guides the Management of Crohn's Patients with Secondary Loss of Response to Adalimumab.

PubMed

Restellini, Sophie; Chao, Che-Yung; Lakatos, Peter L; Aruljothy, Achuthan; Aziz, Haya; Kherad, Omar; Bitton, Alain; Wild, Gary; Afif, Waqqas; Bessissow, Talat

2018-04-13

Managing loss of response (LOR) in Crohn's disase (CD) patients remains challenging. Compelling evidence supports therapeutic drug monitoring (TDM) to guide management in patients on infliximab, but data for other biologics are less robust. We aimed to asses if empiric dose escalation led to improved clinical outcome in addition to TDM-guided optimization in CD patients with LOR to adalimumab (ADA). Retrospective chart review of patients followed between 2014 and 2016 at McGill IBD Center with index TDM for LOR to ADA was performed. Primary outcomes were composite remission at 3, 6, and 12 months in those with empiric adjustments versus TDM-guided optimization. There were 104 patients (54.8% men) who were included in the study. Of this group, 81 patients (77.9%) had serum level (SL) ≥5µg/ml at index TDM with a median value of 12µg/ml (IQR 6.1-16.5). There were 10 patients (9.6%) who had undetectable SL with high anti-ADA antibodies and 48 (46.2%) received empiric escalation. TDM led to change in treatment in 58 patients (55.8%). Among them, 28 (48.3%) had discontinued ADA, 12 (21.7%) had addition of immunomodulator or steroid, and 18 (31%) had ADA dose escalation. Empiric dose escalation before TDM-based optimization was not associated with improved outcomes at 3, 6, and 12 months, irrespective of SL levels. Clear SL cutoff associated with composite remission was not identified. Our data do not support empiric dose adjustment beyond that based on the result of the TDM in patients with LOR to ADA. TDM limits unnecessary dose escalation and provides appropriate treatment strategy without compromising clinical outcomes. 10.1093/ibd/izy044_video1izy044.video15768828880001.

Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Syndikus, Isabel; Morgan, Rachel C.; Sydes, Matthew R., E-mail: ms@ctu.mrc.ac.u

2010-07-01

Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Managementmore » (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade {>=}2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade {>=}2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade {>=}2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.« less

U.S. health care: a conundrum and a challenge.

PubMed

Ciric, Ivan S

2013-12-01

This report was conceived as a contribution to the national debate regarding U.S. health care (HC) and as a means of explaining the challenges facing U.S. HC to the international readers of WORLD NEUROSURGERY. The basic economic concepts pertinent to health care, including fundamentals of economic theories, gross domestic product (GDP), U.S. revenues and expenditures and the U.S. federal deficit and national debt, are discussed at the outset of this study. This is followed by a review of the U.S. health insurance paradigms and a detailed analysis of the escalating cost of U.S. health care. Finally, the efforts designed to reverse the paradigm of escalating health care costs will be discussed. This study reveals that should the U.S. HC cost continue to escalate at the same rate, HC would consume the entire gross domestic product by 2070. The root causes for this trend are overutilization of HC, inappropriate allocation of HC costs at the end of life, defensive medicine, high-end technology and prescription drugs, failure of competitive market forces, and administrative costs, inefficiency, and waste. The proposed means of reversing this paradigm, including the Patient Protection and Affordable Care Act, are discussed in light of their economic and social impact. The reversal of the current paradigm of escalating cost of U.S. HC will require extraordinary leadership across the entire spectrum of HC delivery. It is concluded that neither the Affordable Care Act nor the Path to Prosperity will succeed unless the escalating cost of U.S. HC is reversed. It is hoped that this report contributes to that end. Copyright © 2013 Elsevier Inc. All rights reserved.

Etiologic theories of idiopathic scoliosis. Somatic nervous system and the NOTOM escalator concept as one component in the pathogenesis of adolescent idiopathic scoliosis.

PubMed

Burwell, R G; Dangerfield, P H; Freeman, B J C

2008-01-01

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). In recent years encouraging advances thought to be related to the pathogenesis of AIS have been made in several fields. After reviewing concepts of AIS pathogenesis we formulated a collective model of pathogenesis. The central concept of this collective model is a normal neuro-osseous timing of maturation (NOTOM) system operating in a child's internal world during growth and maturation; this provides a dynamic physiological balance of postural equilibrium continuously renewed between two synchronous, polarized processes (NOTOM escalator) linked through sensory input and motor output, namely: 1) osseous escalator-increasing skeletal size and relative segmental mass, and 2) neural escalator - including the CNS body schema. The latter is recalibrated continuously as the body adjusts to biomechanical and kinematic changes resulting from skeletal enlargement, enabling it to coordinate motor actions. We suggest that AIS progression results from abnormality of the neural and/or osseous components of these normal escalator in time and/or space - as asynchrony and/or asymmetries - which cause a failure of neural systems to control asymmetric growth of a rapidly enlarging and moving adolescent spine. This putative initiating asymmetric growth in the spine is explained in separate papers as resulting from dysfunction of the hypothalamus expressed through the sympathetic nervous system (leptin-sympathetic nervous system concept for AIS pathogenesis). In girls, the expression of AIS may result from disharmony between the somatic and autonomic nervous systems - relative postural maturational delay in the somatic nervous system and hypothalamic dysfunction in the autonomic nervous system, with the conflict being fought out in the spine and trunk of the girl and compounded by biomechanical spinal growth modulation.

Pre-hospital National Early Warning Score (NEWS) is associated with in-hospital mortality and critical care unit admission: A cohort study.

PubMed

Abbott, Tom E F; Cron, Nicholas; Vaid, Nidhi; Ip, Dorothy; Torrance, Hew D T; Emmanuel, Julian

2018-03-01

National Early Warning Score (NEWS) is increasingly used in UK hospitals. However, there is only limited evidence to support the use of pre-hospital early warning scores. We hypothesised that pre-hospital NEWS was associated with death or critical care escalation within the first 48 h of hospital stay. Planned secondary analysis of a prospective cohort study at a single UK teaching hospital. Consecutive medical ward admissions over a 20-day period were included in the study. Data were collected from ambulance report forms, medical notes and electronic patient records. Pre-hospital NEWS was calculated retrospectively. The primary outcome was a composite of death or critical care unit escalation within 48 h of hospital admission. The secondary outcome was length of hospital stay. 189 patients were included in the analysis. The median pre-hospital NEWS was 3 (IQR 1-5). 13 patients (6.9%) died or were escalated to the critical care unit within 48 h of hospital admission. Pre-hospital NEWS was associated with death or critical care unit escalation (OR, 1.25; 95% CI, 1.04-1.51; p = 0.02), but NEWS on admission to hospital was more strongly associated with this outcome (OR, 1.52; 95% CI, 1.18-1.97, p < 0.01). Neither was associated with hospital length of stay. Pre-hospital NEWS was associated with death or critical care unit escalation within 48 h of hospital admission. NEWS could be used by ambulance crews to assist in the early triage of patients requiring hospital treatment or rapid transport. Further cohort studies or trials in large samples are required before implementation.

Aggregate National Early Warning Score (NEWS) values are more important than high scores for a single vital signs parameter for discriminating the risk of adverse outcomes.

PubMed

Jarvis, Stuart; Kovacs, Caroline; Briggs, Jim; Meredith, Paul; Schmidt, Paul E; Featherstone, Peter I; Prytherch, David R; Smith, Gary B

2015-02-01

The Royal College of Physicians (RCPL) National Early Warning Score (NEWS) escalates care to a doctor at NEWS values of ≥5 and when the score for any single vital sign is 3. We calculated the 24-h risk of serious clinical outcomes for vital signs observation sets with NEWS values of 3, 4 and 5, separately determining risks when the score did/did not include a single score of 3. We compared workloads generated by the RCPL's escalation protocol and for aggregate NEWS value alone. Aggregate NEWS values of 3 or 4 (n=142,282) formed 15.1% of all vital signs sets measured; those containing a single vital sign scoring 3 (n=36,207) constituted 3.8% of all sets. Aggregate NEWS values of either 3 or 4 with a component score of 3 have significantly lower risks (OR: 0.26 and 0.53) than an aggregate value of 5 (OR: 1.0). Escalating care to a doctor when any single component of NEWS scores 3 compared to when aggregate NEWS values ≥5, would have increased doctors' workload by 40% with only a small increase in detected adverse outcomes from 2.99 to 3.08 per day (a 3% improvement in detection). The recommended NEWS escalation protocol produces additional work for the bedside nurse and responding doctor, disproportionate to a modest benefit in increased detection of adverse outcomes. It may have significant ramifications for efficient staff resource allocation, distort patient safety focus and risk alarm fatigue. Our findings suggest that the RCPL escalation guidance warrants review. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCath (registered) technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fransson, Per; Bergstroem, Per; Loefroth, Per-Olov

2006-10-01

Purpose: Late side effects were prospectively evaluated up to 5 years after dose-escalated external beam radiotherapy (EBRT) and were compared with a previously treated series with conventional conformal technique. Methods and Materials: Bladder and bowel symptoms were prospectively evaluated with the Prostate Cancer Symptom Scale (PCSS) questionnaire up to 5 years posttreatment. In all, 257 patients completed the questionnaire 5 years posttreatment. A total of 168 patients were treated with the conformal technique at doses <71 Gy, and 195 were treated with the dose-escalated stereotactic BeamCath (registered) technique comprising three dose levels: 74 Gy (n = 68), 76 Gy (nmore » = 74), and 78 Gy (n = 53). Results: For all dose groups analyzed together, 5 years after treatment, urinary starting problems decreased and urinary incontinence increased in comparison to baseline values. No increase in other bladder symptoms or frequency was detected. When comparing dose groups after 5 years, both the 74-Gy and 78-Gy groups reported increased urinary starting problems compared with patients given the conventional dose (<71 Gy). No increased incontinence was seen in the 76-Gy or the 78-Gy groups. Bowel symptoms were slightly increased during the follow-up period in comparison to baseline. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal late side effects after 5 years in comparison to doses <71 Gy. Conclusion: Dose-escalated EBRT with the BeamCath (registered) technique with doses up to 78 Gy is tolerable, and the toxicity profile is similar to that observed with conventional doses <71 Gy.« less

Phase I/II prospective trial of cancer-specific imaging using ultrasound spectrum analysis tissue-type imaging to guide dose-painting prostate brachytherapy.

PubMed

Ennis, Ronald D; Quinn, S Aidan; Trichter, Frieda; Ryemon, Shannon; Jain, Anudh; Saigal, Kunal; Chandrashekhar, Sarayu; Romas, Nicholas A; Feleppa, Ernest J

2015-01-01

To assess the technical feasibility, toxicity, dosimetry, and preliminary efficacy of dose-painting brachytherapy guided by ultrasound spectrum analysis tissue-type imaging (TTI) in low-risk, localized prostate cancer. Fourteen men with prostate cancer who were candidates for brachytherapy as sole treatment were prospectively enrolled. Treatment planning goal was to escalate the tumor dose to 200% with a modest de-escalation of dose to remaining prostate compared with our standard. Primary end points included technical feasibility of TTI-guided brachytherapy and equivalent or better toxicity compared with standard brachytherapy. Secondary end points included dose escalation to tumor regions and de-escalated dose to nontumor regions on the preimplant plan, negative prostate biopsy at 2 years, and freedom from biochemical failure. Thirteen of fourteen men successfully completed the TTI-guided brachytherapy procedure for a feasibility rate of 93%. A software malfunction resulted in switching one patient from TTI-guided to standard brachytherapy. An average of 2.7 foci per patient was demonstrated and treated with an escalated dose. Dosimetric goals on preplan were achieved. One patient expired from unrelated causes 65 days after brachytherapy. Toxicity was at least as low as standard brachytherapy. Two-year prostate biopsies were obtained from six men; five (83%) were definitively negative, one showed evidence of disease with treatment effect, and none were positive. No patients experienced biochemical recurrence after a median followup of 31.5 (24-52) months. We have demonstrated that TTI-guided dose-painting prostate brachytherapy is technically feasible and results in clinical outcomes that are encouraging in terms of low toxicity and successful biochemical disease control. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

microRNA-206 in Rat Medial Prefrontal Cortex Regulates BDNF Expression and Alcohol Drinking

PubMed Central

Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R.; King, Courtney; Heilig, Markus

2014-01-01

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3′-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3′-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3′-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action. PMID:24672003

Stop the escalators: using the built environment to increase usual daily activity.

PubMed

Westfall, John M; Fernald, Doug H

2010-01-01

Obesity is an epidemic in the United States. Two-thirds of the population is overweight and does not get enough exercise. Eastern cities are full of escalators that transport obese Americans to and from the subway. Walking stairs is a moderate activity requiring 3-6 metabolic equivalent tasks (METS) and burning 3.5-7 kcal/min. We determined the caloric expenditure and potential weight change of the population of one eastern city if all the subway riders walked the stairs rather than ride the escalators. There are 5,000,000 daily journeys made on the New York City Subway. Subway entrances include a stairway or escalator of approximately 25 steps. Each step up requires 0.11-0.15 kcals; each step down requires 0.05 kcals. To lose one pound requires burning 3500 kcals. We assumed each rider made a round trip so about 2.5 million individual people ride the subway each day. By walking stairs rather than riding escalators, the riders of the New York Subway would lose more than 2.6 million pounds per year. The average subway rider would lose about one pound per year. While this may sound insignificant, in one decade the average subway rider would lose 10 pounds, effectively reversing the trend in the United States of gaining 10 pounds per decade. This conservative estimate of the number of stairs ascended daily means that subway riders might lose even more weight. We believe that this novel approach might lead to other public and private efforts to increase physical activity such as elevators that only stop on even numbered floors, making stairwells more attractive and well lit, and stopping moving sidewalks. The built environment may support small, incremental changes in usual daily physical activity that can have significant impact on populations and individuals.

microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking.

PubMed

Tapocik, Jenica D; Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R; King, Courtney; Heilig, Markus

2014-03-26

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3'-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3'-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3'-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action.

Wartime Automation Requirements for Maintenance.

DTIC Science & Technology

1982-10-01

of training and humanitarian missions, it is difficult to distinguish between levels of conflict, which may vary due to escalation and de -escalation...the pipeline full of materiel and offset costly requisition and transportation time. The one situation which has changed today is not airbase I Rich...forecast requirements far enough ahead to allow our overtaxed transportation system enough time to move them to the right place at the right time. The

Destined to Die but Not to Wage War: How Existential Threat Can Contribute to Escalation or De-Escalation of Violent Intergroup Conflict

ERIC Educational Resources Information Center

Jonas, Eva; Fritsche, Immo

2013-01-01

War means threat to people's lives. Research derived from terror management theory (TMT) illustrates that the awareness of death leads people to defend cultural ingroups and their worldviews to attain a sense of symbolic immortality and thereby buffer existential anxiety. This can result in hostile effects of mortality salience (MS), such as…

Overcoming the Practical Barriers to Spinal Cord Cell Transplantation for ALS

DTIC Science & Technology

2013-10-01

not be neglected. Moreover, escalating numbers and volumes of injections seem to be associated with lack of accuracy and reflux . Histological...with intact segments. Histological analysis will also determine whether reflux occurs with volume escalation as well as with fast (hand-held...analysis of reflux and transient morbidity with number and volume of injection of hNPCs (Boulis). Create a cell bank of astrocyte restricted

A Checkmate, Not a Stalemate: Turkey Versus the PKK

DTIC Science & Technology

2014-06-01

ETA) cases. The conditions that contribute to a deadlock are the source of much de ate. Stalemates may emanate from the each side’s perception...analyze Turkey’s conflict with the PKK 1 Dean G. ruitt “Escalation and De -escalation in symmetric... De ora G. eeling “ Terrorism in Turkey: History deology Structure and Strategy ” in The PKK: A Decades-Old Brutal Marxist-Leninist Separatist

Macroevolutionary patterns of glucosinolate defense and tests of defense-escalation and resource availability hypotheses.

PubMed

Cacho, N Ivalú; Kliebenstein, Daniel J; Strauss, Sharon Y

2015-11-01

We explored macroevolutionary patterns of plant chemical defense in Streptanthus (Brassicaceae), tested for evolutionary escalation of defense, as predicted by Ehrlich and Raven's plant-herbivore coevolutionary arms-race hypothesis, and tested whether species inhabiting low-resource or harsh environments invest more in defense, as predicted by the resource availability hypothesis (RAH). We conducted phylogenetically explicit analyses using glucosinolate profiles, soil nutrient analyses, and microhabitat bareness estimates across 30 species of Streptanthus inhabiting varied environments and soils. We found weak to moderate phylogenetic signal in glucosinolate classes and no signal in total glucosinolate production; a trend toward evolutionary de-escalation in the numbers and diversity of glucosinolates, accompanied by an evolutionary increase in the proportion of aliphatic glucosinolates; some support for the RAH relative to soil macronutrients, but not relative to serpentine soil use; and that the number of glucosinolates increases with microhabitat bareness, which is associated with increased herbivory and drought. Weak phylogenetic signal in chemical defense has been observed in other plant systems. A more holistic approach incorporating other forms of defense might be necessary to confidently reject escalation of defense. That defense increases with microhabitat bareness supports the hypothesis that habitat bareness is an underappreciated selective force on plants in harsh environments. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

A product of independent beta probabilities dose escalation design for dual-agent phase I trials.

PubMed

Mander, Adrian P; Sweeting, Michael J

2015-04-15

Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Intensive Care, Intense Conflict: A Balanced Approach.

PubMed

Paquette, Erin Talati; Kolaitis, Irini N

2015-01-01

Caring for a child in a pediatric intensive care unit is emotionally and physically challenging and often leads to conflict. Skilled mediators may not always be available to aid in conflict resolution. Careproviders at all levels of training are responsible for managing difficult conversations with families and can often prevent escalation of conflict. Bioethics mediators have acknowledged the important contribution of mediation training in improving clinicians' skills in conflict management. Familiarizing careproviders with basic mediation techniques is an important step towards preventing escalation of conflict. While training in effective communication is crucial, a sense of fairness and justice that may only come with the introduction of a skilled, neutral third party is equally important. For intense conflict, we advocate for early recognition, comfort, and preparedness through training of clinicians in de-escalation and optimal communication, along with the use of more formally trained third-party mediators, as required. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

The Brain Adapts to Dishonesty

PubMed Central

Garrett, Neil; Lazzaro, Stephanie C.; Ariely, Dan; Sharot, Tali

2016-01-01

Dishonesty is an integral part of our social world, influencing domains ranging from finance and politics to personal relationships. Anecdotally, digressions from a moral code are often described as a series of small breaches that grow over time. Here, we provide empirical evidence for a gradual escalation of self-serving dishonesty and reveal a neural mechanism supporting it. Behaviorally, we show that the extent to which participants engage in self-serving dishonesty increases with repetition. Using fMRI we show that signal reduction in the amygdala is sensitive to the history of dishonest behavior, consistent with adaptation. Critically, the extent of amygdala BOLD reduction to dishonesty on a present decision relative to the last, predicts the magnitude of escalation of self-serving dishonesty on the next decision. The findings uncover a biological mechanism that supports a “slippery slope”: what begins as small acts of dishonesty can escalate into larger instances. PMID:27775721

Locked on course: Hydro-Quebec`s commitment to mega-projects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maxwell, J.; Briscoe, F.; Suzuki, Tatsujiro

1997-01-01

Large organizations often escalate their commitments to mega-project development, even after evidence becomes available of adverse environmental consequences or lack of economic feasibility. This escalation of commitment transcends both sectorial and national boundaries. Preeminent examples include controversial nuclear projects in the US, hydroelectric projects like the Three Gorges Dam in China, and transport projects like the Chunnel and the Concorde. In this article, the authors examine the experience of Hydro-Quebec with the Great Whale Project. They argue that Hydro-Quebec escalated its commitment even after serious questions emerged about its environmental impacts and economic feasibility, because of (1) its earlier successmore » with large projects, (2) its engineering culture`s norms for consistency, and (3) its role in the government`s desire for economic and cultural autonomy. Finally, they discuss the changes that are necessary to break commitments to such projects.« less

Using the MCPLXS Generator for Technology Transfer

NASA Technical Reports Server (NTRS)

Moore, Arlene A.; Dean, Edwin B.

1987-01-01

The objective of this paper is to acquaint you with some of the approaches we are taking at Langley to incorporate escalations (or de-escalations) of technology when modeling futuristic systems. Since we have a short turnaround between the time we receive enough descriptive information to start estimating the project and when the estimate is needed (the "we-want-it-yesterday syndrome"), creativity is often necessary. There is not much time available for tool development. It is expedient to use existing tools in an adaptive manner to model the situation at hand. Specifically, this paper describes the use of the RCA PRICE MCPLXS Generator to incorporate technology transfer and technology escalation in estimates for advanced space systems such as Shuttle II and NASA advanced technology vehicles. It is assumed that the reader is familiar with the RCA PRICE family of models as well as the RCA PRICE utility programs such as SCPLX, PARAM, PARASYN, and the MCPLXS Generator.

Dose escalation in permanent brachytherapy for prostate cancer: dosimetric and biological considerations

NASA Astrophysics Data System (ADS)

Li, X. Allen; Wang, Jian Z.; Stewart, Robert D.; Di Biase, Steven J.

2003-09-01

No prospective dose escalation study for prostate brachytherapy (PB) with permanent implants has been reported. In this work, we have performed a dosimetric and biological analysis to explore the implications of dose escalation in PB using 125I and 103Pd implants. The concept of equivalent uniform dose (EUD), proposed originally for external-beam radiotherapy (EBRT), is applied to low dose rate brachytherapy. For a given 125I or 103Pd PB, the EUD for tumour that corresponds to a dose distribution delivered by EBRT is calculated based on the linear quadratic model. The EUD calculation is based on the dose volume histogram (DVH) obtained retrospectively from representative actual patient data. Tumour control probabilities (TCPs) are also determined in order to compare the relative effectiveness of different dose levels. The EUD for normal tissue is computed using the Lyman model. A commercial inverse treatment planning algorithm is used to investigate the feasibility of escalating the dose to prostate with acceptable dose increases in the rectum and urethra. The dosimetric calculation is performed for five representative patients with different prostate sizes. A series of PB dose levels are considered for each patient using 125I and 103Pd seeds. It is found that the PB prescribed doses (minimum peripheral dose) that give an equivalent EBRT dose of 64.8, 70.2, 75.6 and 81 Gy with a fraction size of 1.8 Gy are 129, 139, 150 and 161 Gy for 125I and 103, 112, 122 and 132 Gy for 103Pd implants, respectively. Estimates of the EUD and TCP for a series of possible prescribed dose levels (e.g., 145, 160, 170 and 180 Gy for 125I and 125, 135, 145 and 155 for 103Pd implants) are tabulated. The EUD calculation was found to depend strongly on DVHs and radiobiological parameters. The dosimetric calculations suggest that the dose to prostate can be escalated without a substantial increase in both rectal and urethral dose. For example, increasing the PB prescribed dose from 145 to 180 Gy increases EUD for the rectum by only 3%. Our studies indicate that the dose to urethra can be kept within 100-120% of the prescription dose for all the dose levels studied. In conclusion, dose escalation in permanent implant for localized prostate cancer may be advantageous. It is dosimetrically possible to increase dose to prostate without a substantial increase in the dose to the rectum and urethra. Based on the results of our studies, a prospective dose escalation trial for prostate permanent implants has been initiated at our institution.

Army Support of Military Cyberspace Operations: Joint Contexts and Global Escalation Implications

DTIC Science & Technology

2015-01-01

Contexts and Global Escalation Implications 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...the command under the leadership of Lieu- tenant General Rhett Hernandez as well as its current operations led by Lieutenant General Edward Cardon ...operations led by Lieutenant General Edward Cardon . This includes a brief review of recent efforts to establish Fort Gordon, Georgia as the center of

Nuclear Weapons and Coercive Escalation in Regional Conflicts: Lessons from North Korea and Pakistan

DTIC Science & Technology

2014-11-01

brinkmanship relies on apparently suicidal and self-destructive tactics. Pakistan is often described as a country that “negotiates with a gun to its own...On 13 December 2001, five militants armed with plastic explosives, suicide vests, assault rifles, and grenades infiltrated the secure perimeter...is true, it is possible that the temptation to engage in coercive escalation will become tempered over time as relatively new nuclear powers come to

Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial

PubMed Central

Hassenbusch, Samuel J; Nardone, Emilio M; Levin, Victor A; Leeds, Norman; Pietronigro, Dennis

2003-01-01

Abstract DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the intratumoral treatment of gliomas. The ethanol solvent vehicle facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent BCNU. We conducted a phase I/II dose escalation study of DTI-015 in 40 heavily pretreated patients with inoperable recurrent malignant glioma. The study goals were to establish a maximally tolerated dose (MTD) for DTI-015 and assess its safety and activity. Patients received stereotactic intratumoral injection of DTI-015 under magnetic resonance imaging guidance. Dose escalation was performed in two phases. First, DTI-015 volume was escalated at a set BCNU concentration of 12.5 mg/ml; second, BCNU mg dose was escalated by increasing BCNU concentration to 30, 45, 60, and 75 mg/ml. A MTD of 5 ml and 240 mg was established. Twenty-five of 28 DTI-015 treatments (89%) using ≤MTD were administered safely without producing high-grade drug-related adverse events. Median survival for GBM patients administered DTI-015 at ≤MTD was 55 weeks. Magnetic resonance imaging demonstrated stable disease in 72% of evaluable patients with a median of 10.5 weeks. The results suggest that DTI-015 administered at ≤MTD is well tolerated and active in patients with inoperable recurrent GBM. PMID:12659665

Social learning requires plasticity enhanced by fluoxetine through prefrontal Bdnf-TrkB signaling to limit aggression induced by post-weaning social isolation

PubMed Central

Umemori, Juzoh; Tóth, Máté; Biró, László; Miskolczi, Christina; Balázsfi, Diána; Zelena, Dóra; Castrén, Eero

2017-01-01

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression. PMID:28685757

Trajectories of Children's Social Interactions with their Infant Sibling in the First Year: A Multi-Dimensional Approach

PubMed Central

Oh, Wonjung; Volling, Brenda L.; Gonzalez, Richard

2015-01-01

Individual differences in longitudinal trajectories of children's social behaviors toward their infant sibling were examined simultaneously across multiple social dimensions: Positive engagement (moving toward), Antagonism (moving against), and Avoidance (moving away). Three distinct social patterns were identified: (C1) Positively-Engaged (n=107, 50%); (C2) Escalating-Antagonism (n=90, 42%); and (C3) Early-Onset Antagonism (n=16, 8%). Children in the positively-engaged class had high levels of positive engagement with their infant siblings, coupled with low levels of antagonism and avoidance. The escalating-antagonism class was positively engaged in sibling interaction with a steep escalation in antagonistic behavior and avoidance from 4 to 12 months. Children in the early-onset antagonism class displayed the highest level of antagonistic behavior starting as early as 4 months, and became increasingly avoidant over time. A path model, guided by a process × person × context × time model, revealed that low parental self-efficacy heightened by parenting stress and children's dysregulated temperament was directly related to the escalating-antagonism pattern. Punitive parenting in response to children's antagonistic behavior increased the likelihood of being in the early-onset antagonism class. Together, the results highlighted heterogeneity in the earliest emergence of sibling interaction patterns and the interplay of child and parent factors in predicting distinct sibling interaction trajectory patterns. PMID:25664367

Crises Management in the Oil and Gas Industry: The Niger Delta Experience

NASA Astrophysics Data System (ADS)

Odemene, Glory C.

The Niger Delta crises escalated beyond the borders of the Nigerian nation to become an issue that affected individuals and corporations around the world. This study led to the discovery of how the local crises escalated with international implications. This discovery was accomplished by addressing how the Niger Delta crises escalated from villages to international scenes, with notable impacts on the environment, health, safety, security, and financial segments of local, international, private, and corporate entities. Using Sweeny's crisis decision theory and Lazarus and Folkman's coping theory, the study considered the coping strategies of community members, the decisions, and actions they took in response to the management approaches of the government and the oil and gas companies (OGCs). This qualitative study utilized historical narrative to collect data by interviewing 4 participants who lived and worked in the region during the crises. NVivo was used for manual and automatic coding of data, as well as for categorization and connection of codes. Content analysis of identified codes and categories revealed the themes and trends in the experiences narrated by participants. Findings include the root causes, trend of escalation, and management strategies of the government and the OGCs that influenced the crises. These findings will help to influence policies and practices in the region and enhance effective management of current and emerging conflicts, with possibilities of restoring stability and security in the areas and in the nation at large.

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

PubMed Central

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer.

PubMed

Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-02-01

To observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Dose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Conflict matrix : Risk management tool in the operating room].

PubMed

Andel, D; Markstaller, K; Andel, H

2017-05-01

In business conflicts have long been known to have a negative effect on costs and team performance. In medicine this aspect has been widely neglected, especially when optimizing processes for operating room (OR) management. In the multidisciplinary setting of OR management, shortcomings in rules for decision making and lack of communication result in members perceiving themselves as competitors in the patient's environment rather than acting as art of a multiprofessional team. This inevitably leads to the emergence and escalation of conflicts. We developed a conflict matrix to provide an inexpensive and objective way for evaluating the level of escalation of conflicts in a multiprofessional working environment, such as an OR. The senior members of all involved disciplines were asked to estimate the level of conflict escalation between the individual professional groups on a scale of 0-9. By aggregating the response data, an overview of the conflict matrix within this OR section was created. No feedback was received from 1 of the 11 contacted occupational groups. By color coding the median, minimum and maximum values of the retrieved data, an intuitive overview of the escalation levels of conflict could be provided. The value range of all feedbacks was between 0 and 6. Estimation of the escalation levels differed widely within one category, showing a range of up to 6 (out of 6) levels. The presented assessment using a conflict matrix is a simple and cost-effective method to assess the conflict landscape, especially in multidisciplinary environments, such as OR management. The chance of conflict prevention or the early recognition of existing conflicts represents an enormous potential for cost and risk saving and might have positive long-term effects by building a culture of conflict prevention at the workplace and a positive influence on interdisciplinary cooperation in this working environment.

Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Felix Y., E-mail: ffeng@med.umich.edu; Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan; Blas, Kevin

2013-05-01

Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64more » months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.« less

Effect of a simple dose-escalation schedule on tramadol tolerability : assessment in the clinical setting.

PubMed

Tagarro, I; Herrera, J; Barutell, C; Díez, M C; Marín, M; Samper, D; Busquet, C; Rodríguez, M J

2005-01-01

To assess the effect of a very simple dose-escalation schedule on tramadol tolerability in clinical practice. This schedule consists of starting treatment with sustained-release tramadol 50mg twice daily, and escalating the dose around 7 days later to 100mg twice daily. Data from 1925 outpatients with non-malignant chronic pain were collected in this multicentre, prospective, comparative, non-randomised, open, observational study. A total of 1071 patients (55.6%) were included in the dose-escalation group (50mg group) and 854 patients (44.4%) in the control group (sustained-release tramadol 100mg twice daily; 100mg group). The proportion of patients who interrupted tramadol treatment due to the occurrence of adverse reactions was significantly lower in the 50mg group (5.6%) than in the 100mg group (12.6%) [p = 0.001]. In line with this, the proportion of patients who experienced at least one adverse reaction was significantly lower in the 50mg group (18.4%) than in the 100mg group (30.4%) [p = 0.001] and, interestingly, the two most frequently reported adverse reactions, nausea and dizziness, were found with a significantly lower frequency in the 50mg group (p < 0.001). Multivariate analysis showed that the risk of safety-related treatment cessations was 2.3 times higher in the 100mg group than in the 50mg group, and 2.2 times higher in females than in males. The two treatments were equally effective in reducing pain intensity (p = 0.121), measured as a reduction in pain score obtained by means of a visual analogue scale. The instauration of tramadol treatment, starting with sustained-release 50mg capsules twice daily and escalating the dose some days later to 100mg twice daily, was shown to be an effective and easy way to improve tramadol tolerability in clinical practice, whilst maintaining its analgesic efficacy.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

A novel concept for tumour targeting with radiation: Inverse dose-painting or targeting the "Low Drug Uptake Volume".

PubMed

Yaromina, Ala; Granzier, Marlies; Biemans, Rianne; Lieuwes, Natasja; van Elmpt, Wouter; Shakirin, Georgy; Dubois, Ludwig; Lambin, Philippe

2017-09-01

We tested a novel treatment approach combining (1) targeting radioresistant hypoxic tumour cells with the hypoxia-activated prodrug TH-302 and (2) inverse radiation dose-painting to boost selectively non-hypoxic tumour sub-volumes having no/low drug uptake. 18 F-HX4 hypoxia tracer uptake measured with a clinical PET/CT scanner was used as a surrogate of TH-302 activity in rhabdomyosarcomas growing in immunocompetent rats. Low or high drug uptake volume (LDUV/HDUV) was defined as 40% of the GTV with the lowest or highest 18 F-HX4 uptake, respectively. Two hours post TH-302/saline administration, animals received either single dose radiotherapy (RT) uniformly (15 or 18.5Gy) or a dose-painted non-uniform radiation (15Gy) with 50% higher dose to LDUV or HDUV (18.5Gy). Treatment plans were created using Eclipse treatment planning system and radiation was delivered using VMAT. Tumour response was quantified as time to reach 3 times starting tumour volume. Non-uniform RT boosting tumour sub-volume with low TH-302 uptake (LDUV) was superior to the same dose escalation to HDUV (p<0.0001) and uniform RT with the same mean dose 15Gy (p=0.0077). Noteworthy, dose escalation to LDUV required on average 3.5Gy lower dose to the GTV to achieve similar tumour response as uniform dose escalation. The results support targeted dose escalation to non-hypoxic tumour sub-volume with no/low activity of hypoxia-activated prodrugs. This strategy applies on average a lower radiation dose and is as effective as uniform dose escalation to the entire tumour. It could be applied to other type of drugs provided that their distribution can be imaged. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

PubMed

Rasmussen, Jacob H; Håkansson, Katrin; Vogelius, Ivan R; Aznar, Marianne C; Fischer, Barbara M; Friborg, Jeppe; Loft, Annika; Kristensen, Claus A; Bentzen, Søren M; Specht, Lena

2016-07-01

The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTVPET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTVPET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTVPET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTVPET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist. Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects. With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

PubMed

Pappas, Dimitrios A; John, Ani; Curtis, Jeffrey R; Reed, George W; Karki, Chitra; Magner, Robert; Kremer, Joel M; Shewade, Ashwini; Greenberg, Jeffrey D

2016-06-01

In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. ClinicalTrials.gov identifier, NCT01625650.

Stop the escalators: using the built environment to increase usual daily activity

PubMed Central

Westfall, John M; Fernald, Doug H

2010-01-01

Background Obesity is an epidemic in the United States. Two-thirds of the population is overweight and does not get enough exercise. Eastern cities are full of escalators that transport obese Americans to and from the subway. Walking stairs is a moderate activity requiring 3–6 metabolic equivalent tasks (METS) and burning 3.5–7 kcal/min. We determined the caloric expenditure and potential weight change of the population of one eastern city if all the subway riders walked the stairs rather than ride the escalators. Methods There are 5,000,000 daily journeys made on the New York City Subway. Subway entrances include a stairway or escalator of approximately 25 steps. Each step up requires 0.11–0.15 kcals; each step down requires 0.05 kcals. To lose one pound requires burning 3500 kcals. We assumed each rider made a round trip so about 2.5 million individual people ride the subway each day. Results By walking stairs rather than riding escalators, the riders of the New York Subway would lose more than 2.6 million pounds per year. Discussion The average subway rider would lose about one pound per year. While this may sound insignificant, in one decade the average subway rider would lose 10 pounds, effectively reversing the trend in the United States of gaining 10 pounds per decade. This conservative estimate of the number of stairs ascended daily means that subway riders might lose even more weight. We believe that this novel approach might lead to other public and private efforts to increase physical activity such as elevators that only stop on even numbered floors, making stairwells more attractive and well lit, and stopping moving sidewalks. The built environment may support small, incremental changes in usual daily physical activity that can have significant impact on populations and individuals. PMID:27774003

Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talleur, Aimee C.; Navid, Fariba; Spunt, Sheri L.

Purpose: To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS). Methods and Materials: Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resectionmore » received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients. Results: Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group. Conclusions: Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.« less

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

PubMed

Skoetz, Nicole; Will, Andrea; Monsef, Ina; Brillant, Corinne; Engert, Andreas; von Tresckow, Bastian

2017-05-25

There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) SELECTION CRITERIA: We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression.We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events.Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. We screened 1796 records and identified five eligible trials in total i.e. one trial could be added on the previous review. These trials included only adults (16 to 65 years of age). We included all five trials with 3427 people in the meta-analyses: the HD9 and HD14 trials were co-ordinated in Germany, the HD2000 and GSM-HD trials were performed in Italy and the EORTC 20012 was conducted in Belgium. The overall risk of performance and detection bias was low for overall survival (OS), but was high for other outcomes, as therapy blinding was not feasible. The remaining 'Risk of bias' domains were low and unclear.All trials reported results for OS and progression-free survival (PFS). In contrast to the our first published review (2011) the addition of results from the EORTC 20012 BEACOPP escalated increases OS (3142 participants; HR 0.74 (95% confidence interval (CI) 0.57 to 0.97; high-quality evidence). This means that only 90 (70 to 117) patients will die after five years in the BEACOPP escalated arm compared to 120 in the ABVD arm. This survival advantage is also reflected in an increased PFS with BEACOPP escalated (3142 participants; HR 0.54 (95% CI 0.45 to 0.64); moderate-quality evidence), meaning that after five years only 144 (121 to 168) patients will experience a progress, relapse or death in the BEACOPP escalated arm compared to 250 in the ABVD arm.There is no evidence for a difference for treatment-related mortality (2700 participants, RR 2.15 (95% CI = 0.93 to 4.95), low-quality evidence).Although the occurrence of MDS or AML may increase with BEACOPP escalated (3332 participants, RR 3.90 (95% CI 1.36 to 11.21); low-quality evidence)), there is no evidence for a difference between both regimens for overall secondary malignancies (3332 participants, RR 1.00 (95% CI 0.68 to 1.48), low-quality evidence). However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours which would not be expected to show significance until around 15 years after treatment.We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured (106 participants, RR 1.37 (95% CI 0.83 to 2.26), very low-quality evidence). This is a very small sample, and the age of the patients was not detailed. No analysis of male fertility was provided.Five trials reported adverse events and the analysis shows that the escalated BEACOPP regimens probably causes more haematological toxicities WHO grade III or IV ((anaemia: 2425 participants, RR 10.67 (95% CI 7.14 to 15.93); neutropenia: 519 participants, RR 1.80 (95% CI 1.52 to 2.13); thrombocytopenia: 2425 participants, RR 18.12 (95% CI 11.77 to 27.92); infections: 2425 participants, RR 3.73 (95% CI 2.58 to 5.38), all low-quality evidence).Only one trial (EORTC 20012) planned to assess quality of life, however, no results were reported. This meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does for the first time suggest a survival benefit. However, it is clear from this review that BEACOPP escalated may be more toxic that ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet.

Preventing Escalation in the South China Sea Disputed Waters: A Comparative Study of Republic of the Philippines and Socialist Republic of Vietnam

DTIC Science & Technology

2015-03-01

among claimants’ civilian and military maritime forces in the South China Sea, and there are few studies of how the lack of civil-military cooperation...ESCALATION IN THE SOUTH CHINA SEA DISPUTED WATERS: A COMPARATIVE STUDY OF REPUBLIC OF THE PHILIPPINES AND SOCIALIST REPUBLIC OF VIETNAM by Askari...SOUTH CHINA SEA DISPUTED WATERS: A COMPARATIVE STUDY OF REPUBLIC OF THE PHILIPPINES AND SOCIALIST REPUBUC OF VIETNAM 6. AUTHOR(S) Askari 7

KCNSC Automated RAIL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Branson, Donald

The KCNSC Automated RAIL (Rolling Action Item List) system provides an electronic platform to manage and escalate rolling action items within an business and manufacturing environment at Honeywell. The software enables a tiered approach to issue management where issues are escalated up a management chain based on team input and compared to business metrics. The software manages action items at different levels of the organization and allows all users to discuss action items concurrently. In addition, the software drives accountability through timely emails and proper visibility during team meetings.

Understanding Children’s Emotional Processes and Behavioral Strategies in the Context of Marital Conflict

PubMed Central

Koss, Kalsea J.; George, Melissa R. W.; Bergman, Kathleen N.; Cummings, E. Mark; Davies, Patrick T.; Cicchetti, Dante

2011-01-01

Marital conflict is a distressing context in which children must regulate their emotion and behavior, however, the associations between the multidimensionality of conflict and children’s regulatory processes needs to be examined. The current study examined differences in children’s (n = 207; M = 8.02 years) emotions (mad, sad, scared, and happy) and behavioral strategies to regulate conflict exposure during resolved, unresolved, escalating, and child-rearing marital conflict vignettes. Children’s cortisol levels were assessed in relation to child-rearing and resolved conflict vignettes. Anger and sadness were associated with escalating and child-rearing conflicts; fearfulness was related to escalating and unresolved conflicts. Children’s happiness was associated with resolution. Anger was associated with children’s strategies to stop conflict; whereas, sadness was associated with monitoring and avoidant strategies. Cortisol recovery moderated the link between fearfulness and behavioral regulation. These results highlight the importance of children’s emotions and regulatory processes in understanding the impact of marital conflict. PMID:21397249

nuSTORM Costing document

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bross, Alan D.

2013-10-01

Detailed costing of the nuSTORM conventional facilities has been done by the Fermilab Facilities Engineering Services Section (FESS) and is reported on in the nuSTORM Project Definition Report (PDR) 6-13-1. Estimates for outfitting the primary proton beam line, the target station, the pion capture/transport line and decay ring are based on either experience from existing Fermilab infrastructure (NuMI) or is based on the detailed costing exercises for DOE CD-1 approval for future experiments (mu2e and LBNE). The detector costing utilized the Euronu costing for the Neutrino Factory Magnetized Iron Neutrino Detector (MIND), extrapolations from MINOS as-built costs and from recentmore » vendor quotes. Costs included all manpower and are fully burdened (FY2013 dollars). The costs are not escalated, however, beyond the 5-year project timeline, since a project start for nuSTORM is unknown. Escalation can be estimated from various models (see Figure 1). LBNE has used the Jacob’s model to determine their cost escalation.« less

Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

NASA Astrophysics Data System (ADS)

Pervez, Nadeem

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

A sequential learning analysis of decisions in organizations to escalate investments despite continuing costs or losses

PubMed Central

Goltz, Sonia M.

1992-01-01

Reinforcement process may underlie decisions frequently found in organizations to escalate investments of time, money and other resources in strategies (e.g., product development, capital investment, plant expansion) that do not result in immediate reinforces. Whereas cognitive biases have been proffered in previous explanations, the present analysis suggested that this persistence is a form of resistance to extinction arising from experiences with past investments that were variably reinforced. This explanation was examined in two experiments by varying the pattern of returns and losses subjects experienced for investment decisions prior to experiencing a series losses. Consistent with the proposed explanation, two conditions resulted in higher levels of recommitment during continuous losses: (a) training using a variable schedule of partial reinforcement, and (b) no training on the task. Results indicate that behavior analysis can be used to understand and control situations in organizations that are prone to escalation, such as investments in the research and development of new product lines and extensions of further loans to customers. PMID:16795785

Terrorist Attacks Escalate in Frequency and Fatalities Preceding Highly Lethal Attacks

PubMed Central

Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G.; Schimel, Jeff; Webber, David

2014-01-01

Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates–both in the number of people killed per attack and in the frequency of attacks–leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack. PMID:24755753

Flu, risks, and videotape: escalating fear and avoidance.

PubMed

Rosoff, Heather; John, Richard S; Prager, Fynnwin

2012-04-01

While extensive risk perception research has focused on emotions, cognitions, and behavior at static points in time, less attention has been paid to how these variables might change over time. This study assesses how negative affect, threat beliefs, perceived risk, and intended avoidance behavior change over the course of an escalating biological disaster. A scenario simulation methodology was used that presents respondents with a video simulation of a 15-day series of local news reports to immerse respondents in the developing details of the disaster. Systemic manipulation of the virus's causal origin (terrorist attack, medical lab accident, unknown) and the respondent's proximity to the virus (local vs. opposite coast) allowed us to investigate the dynamics of public response. The unfolding scenario was presented in discrete episodes, allowing responses to be tracked over the episodes. The sample includes 600 respondents equally split by sex and by location, with half in the Washington, DC area, and half in the Los Angeles area. The results showed respondents' reactions to the flu epidemic increased as the disaster escalated. More importantly, there was considerable consistency across respondents' emotional, cognitive, and behavioral responses to the epidemic over the episodes. In addition, the reactions of respondents proximally closer to the epidemic increased more rapidly and with greater intensity than their distant counterparts. Finally, as the flu epidemic escalated, both terrorist and accidental flu releases were perceived as being less risky and were less likely to lead to avoidance behavior compared to the unknown flu release. © 2012 Society for Risk Analysis.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

PubMed

Hughes, Timothy P; Munhoz, Eduardo; Aurelio Salvino, Marco; Ong, Tee Chuan; Elhaddad, Alaa; Shortt, Jake; Quach, Hang; Pavlovsky, Carolina; Louw, Vernon J; Shih, Lee-Yung; Turkina, Anna G; Meillon, Luis; Jin, Yu; Acharya, Sandip; Dalal, Darshan; Lipton, Jeffrey H

2017-10-01

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188). © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

PubMed

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy.

PubMed

Kumar, Sameera S; Higgins, Kristin A; McGarry, Ronald C

2017-01-01

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.

Escalation of polymerization in a thermal gradient

PubMed Central

Mast, Christof B.; Schink, Severin; Gerland, Ulrich; Braun, Dieter

2013-01-01

For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then could self-replicating ribozymes appear, for which recent experiments suggest a minimal length of 200 nt? Here, we demonstrate a mechanism to bridge this gap: the escalated polymerization of nucleotides by a spatially confined thermal gradient. The gradient accumulates monomers by thermophoresis and convection while retaining longer polymers exponentially better. Polymerization and accumulation become mutually self-enhancing and result in a hyperexponential escalation of polymer length. We describe this escalation theoretically under the conservative assumption of reversible polymerization. Taking into account the separately measured thermophoretic properties of RNA, we extrapolate the results for primordial RNA polymerization inside a temperature gradient in pores or fissures of rocks. With a dilute, nanomolar concentration of monomers the model predicts that a pore length of 5 cm and a temperature difference of 10 K suffice to polymerize 200-mers of RNA in micromolar concentrations. The probability to generate these long RNAs is raised by a factor of >10600 compared with polymerization in a physical equilibrium. We experimentally validate the theory with the reversible polymerization of DNA blocks in a laser-driven thermal trap. The results confirm that a thermal gradient can significantly enlarge the available sequence space for the emergence of catalytically active polymers. PMID:23630280

Effectiveness of training on de-escalation of violence and management of aggressive behavior faced by health care providers in a public sector hospital of Karachi

PubMed Central

Baig, Lubna; Tanzil, Sana; Shaikh, Shiraz; Hashmi, Ibrahim; Khan, Muhammad Arslan; Polkowski, Maciej

2018-01-01

Background & Objective: Considering high burden of violence against healthcare workers in Pakistan APPNA Institute of Public Health developed a training to prevent reactive violence among healthcare providers. The purpose of this training was to equip healthcare providers with skills essential to control aggressive behaviors and prevent verbal and non-verbal violence in workplace settings. This study assesses the effectiveness of training in prevention, de-escalation and management of violence in healthcare settings. Methods: A quasi-experimental study was conducted in October, 2016 using mixed method concurrent embedded design. The study assessed effectiveness of de-escalation trainings among health care providers working in emergency and gynecology and obstetrics departments of two teaching hospitals in Karachi. Quantitative assessment was done through structured interviews and qualitative through Focus Group Discussions. Healthcare providers` confidence in coping with patient aggression was also measured using a standard validated tool”. Results: The overall self-perceived mean score of Confidence in Coping with Patient Aggression Instrument “(CCPAI)” scale was significantly higher in intervention group (Mean= 27.49, SD=3.53) as compared to control group (Mean= 23.92, SD=4.52) (p<0.001). No statistically significant difference was observed between intervention and control groups with regard to frequency of violence faced by HCPs post training and major perpetrators of violence.. Conclusion: De-escalation of violence training was effective in improving confidence of healthcare providers in coping with patient aggression. PMID:29805396

Phylogenetic escalation and decline of plant defense strategies

PubMed Central

Agrawal, Anurag A.; Fishbein, Mark

2008-01-01

As the basal resource in most food webs, plants have evolved myriad strategies to battle consumption by herbivores. Over the past 50 years, plant defense theories have been formulated to explain the remarkable variation in abundance, distribution, and diversity of secondary chemistry and other defensive traits. For example, classic theories of enemy-driven evolutionary dynamics have hypothesized that defensive traits escalate through the diversification process. Despite the fact that macroevolutionary patterns are an explicit part of defense theories, phylogenetic analyses have not been previously attempted to disentangle specific predictions concerning (i) investment in resistance traits, (ii) recovery after damage, and (iii) plant growth rate. We constructed a molecular phylogeny of 38 species of milkweed and tested four major predictions of defense theory using maximum-likelihood methods. We did not find support for the growth-rate hypothesis. Our key finding was a pattern of phyletic decline in the three most potent resistance traits (cardenolides, latex, and trichomes) and an escalation of regrowth ability. Our neontological approach complements more common paleontological approaches to discover directional trends in the evolution of life and points to the importance of natural enemies in the macroevolution of species. The finding of macroevolutionary escalating regowth ability and declining resistance provides a window into the ongoing coevolutionary dynamics between plants and herbivores and suggests a revision of classic plant defense theory. Where plants are primarily consumed by specialist herbivores, regrowth (or tolerance) may be favored over resistance traits during the diversification process. PMID:18645183

Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for {sup 18}F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teoh, May, E-mail: m.teoh@nhs.net; Beveridge, Sabeena; Wood, Katie

2013-04-01

Fluorine-18-fluorodeoxyglucose-positron emission tomography ({sup 18}F-FDG-PET)–guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to {sup 18}F-FDG-PET–positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gymore » in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI{sub Paddick}) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI{sub Paddick} scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8–49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). {sup 18}F-FDG-PET–guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.« less

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.

PubMed

Holly, Elizabeth N; Boyson, Christopher O; Montagud-Romero, Sandra; Stein, Dirson J; Gobrogge, Kyle L; DeBold, Joseph F; Miczek, Klaus A

2016-04-06

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h "binge." VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. Copyright © 2016 the authors 0270-6474/16/364094-13$15.00/0.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area

PubMed Central

Boyson, Christopher O.; Montagud-Romero, Sandra; Stein, Dirson J.; Gobrogge, Kyle L.; DeBold, Joseph F.; Miczek, Klaus A.

2016-01-01

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats. In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h “binge.” VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. SIGNIFICANCE STATEMENT Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. PMID:27053215

The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills?

PubMed

Sridharan, Prasanna; Chamberlain, Ronald S

2013-12-01

Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the context of an underlying infectious process, and is associated with high rates of morbidity and mortality, particularly when initial therapy is delayed. Numerous biomarkers, including but not limited to cytokines (interleukins-2 and -6 [IL-2, IL-6] and tumor necrosis factor-α [TNF-α]), leukotrienes, acute-phase proteins (C-reactive protein [CRP]), and adhesion molecules, have been evaluated and rejected as unsuitable for the diagnosis of sepsis, predicting its severity, and guiding its treatment. Most recently, procalcitonin (PCT) has been suggested as a novel biomarker that may be useful in guiding therapeutic decision making in the management of sepsis. This article assesses critically the published literature on the clinical utility of PCT concentrations for guiding the treatment of sepsis in adult patients. A comprehensive search of all published studies of the use of serum concentrations of PCT to guide the treatment of sepsis in adult patients (1996 to 2011) was conducted with PubMed and Google Scholar. The search focused on the value of PCT concentrations to guide the diagnosis, prognosis, monitoring, and escalation and de-escalation of antbiotic therapy in these patients. Keywords searched included "procalcitonin," "sepsis," "sepsis biomarker," "sepsis diagnosis," "sepsis prognosis," "sepsis mortality," "antibiotic escalation," "antibiotic de-escalation," "antibiotic duration," and "antimicrobial stewardship." Forty-six trials evaluating the efficacy of PCT concentrations in diagnosing sepsis have been published, with 39 of these trials yielding positive results and 7 yielding negative results. Wanner et al. published the largest study (n=405) demonstrating that peak PCT concentrations occur early after injury in both patients with sepsis and those with multiple organ dysfunction syndrome (MODS). Among 17 trials assessing the prognostic value of PCT concentrations with regard to clinical outcome and morbidity, 12 trials yielded positive results and five showed negative or equivocal results. Reith et al. published the largest study of the prognostic use of PCT concentrations (n=246), demonstrating that median PCT values on post-operative days (POD) one, four, and 10 were predictive of mortality in patients with abdominal sepsis (p<0.01). Among 14 trials of the utility of PCT concentrations for establishing an infectious cause of sepsis, 13 yielded positive results and only one yielded negative results. The largest study of this use of PCT concentrations, conducted by Baykut et al. (n=400), evaluated these concentrations in post-operative patients with infection, and demonstrated that concentrations of PCT remained elevated until POD 4, with a second increase observed between POD 4 and POD 6. In uninfected patients, PCT concentrations began to decrease on POD 2. Only a single study has assessed the utility of PCT concentrations in guiding the escalation of antibiotic therapy, and its results were negative. Specifically, Jensen et al. (n=1,200) compared a PCT-guided antibiotic escalation strategy with the standard of care for sepsis and found no difference in outcomes. They also found that the PCT group had a longer average stay in the intensive care unit (ICU), greater rates of mechanical ventilation, and a decreased estimated glomerular filtration rate (eGFR). Among four trials focusing on PCT concentrations and antibiotic de-escalation, all showed positive results with the measurement of PCT concentrations. The largest such study, by Bouadma et al. (n=621), demonstrated a four-day decrease in antibiotic duration when PCT concentrations were used to guide therapy relative to the study arm given the standard of care, with no increase in mortality (p=0.003). The diagnostic value of serum PCT concentrations for discriminating among SIRS, sepsis, severe sepsis, and septic shock remains to be established. Although higher PCT concentrations suggest a systemic bacterial infection as opposed to a viral, fungal, or inflammatory etiology of sepsis, serum PCT concentrations do not correlate with the severity of sepsis or with mortality. At present, PCT concentrations are solely investigational with regard to determining the timing and appropriateness of escalation of antimicrobial therapy in sepsis. Nevertheless, serum PCT concentrations have established utility in monitoring the clinical response to medical and surgical therapy for sepsis, and in surveillance for the development of sepsis in burn and ICU patients, and may have a role in guiding the de-escalation of antibiotic therapy.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.

PubMed

Clark, Richard E; Polydoros, Fotios; Apperley, Jane F; Milojkovic, Dragana; Pocock, Christopher; Smith, Graeme; Byrne, Jenny L; de Lavallade, Hugues; O'Brien, Stephen G; Coffey, Tony; Foroni, Letizia; Copland, Mhairi

2017-07-01

Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. Newcastle University and Bloodwise. Copyright © 2017 Elsevier Ltd. All rights reserved.

Baclofen has opposite effects on escalation of cocaine self-administration: increased intake in rats selectively bred for high (HiS) saccharin intake and decreased intake in those selected for low (LoS) saccharin intake

PubMed Central

Holtz, Nathan A.; Carroll, Marilyn E.

2011-01-01

Rats selectively bred for high saccharin intake (HiS) self-administer more cocaine, escalate their cocaine intake during long access, and reinstate cocaine seeking at higher levels than those bred for low saccharin intake (LoS). The present study was conducted to determine if baclofen, an agonist at the GABAb receptor, has differential effects on the escalation of i.v. cocaine intake and reinstatement of cocaine-seeking in HiS and LoS rats. HiS and LoS rats self-administered cocaine during a 2-h daily short-access (ShA) phase for 3 days and then long-access (LgA) sessions for 21 days followed by a second ShA phase. One group of HiS and LoS rats received i.p. injections of 2.5 mg/kg baclofen (HiS+B and LoS+B, respectively), and other groups of HiS and LoS rats received saline (HiS+Sal and LoS+Sal) before each daily session. In a second experiment, HiS and LoS rats self-administered i.v. cocaine during 2-h sessions for 14 days followed by a 21-day extinction period. Baclofen (2.5 mg/kg, i.p.) or saline was administered before saline- or cocaine-primed reinstatement sessions. The HiS+B group escalated their cocaine self-administration and had increased cocaine infusions in the post-LgA ShA phase. The LoS+B group self-administered less cocaine throughout the entire LgA period compared to the LoS+Sal or HiS groups. Baclofen attenuated reinstatement of cocaine seeking in both the HiS and LoS rats with no phenotype differences. Baclofen had opposite effects on cocaine intake in HiS and LoS rats during escalation; HiS increased and LoS decreased intake. These results suggest that treatment effects might vary with individual differences (HiS vs. LoS) and the phase of drug-motivated behavior that is modeled. PMID:21924281

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

What are the critical steps in processing blood cultures? A prospective audit evaluating current practice of reporting blood cultures in a centralised laboratory serving secondary care hospitals.

PubMed

Meda, Manjula; Clayton, James; Varghese, Reela; Rangaiah, Jayakeerthi; Grundy, Clive; Dashti, Farnaz; Garner, David; Groves, Katherine; Fitzmaurice, Karen; Hutley, E

2017-04-01

To assess current procedures of processing positive blood cultures against national standards with an aim to evaluate its clinical impact and to determine the utility of currently available rapid identification and susceptibility tests in processing of blood cultures. Blood cultures from three secondary care hospitals, processed at a centralised laboratory, were prospectively audited. Data regarding processing times, communication with prescribers, changes to patient management and mortality within 30 days of a significant blood culture were collected in a preplanned pro forma for a 4-week period. Of 2206 blood cultures, 211 positive blood cultures flagged positive. Sixty-nine (3.1%) of all cultures were considered to be contaminated. Fifty per cent of blood cultures that flagged positive had a Gram stain reported within 2 hours. Two (0.99%) patients with a significant bacteraemia had escalation of antimicrobial treatment at the point of reporting the Gram stain that was subsequently deemed necessary once sensitivity results were known. Most common intervention was de-escalation of therapy for Gram-positive organisms at the point of availability of pathogen identification (25.6% in Gram positive vs 10% in Gram negative; p=0.012). For Gram-negative organisms, the most common intervention was de-escalation of therapy at the point of availability of sensitivity results (43% in Gram negatives vs 17.9% in Gram positive; p=0.0097). Overall mortality within 30 days of a positive blood culture was 10.9% (23/211). Antibiotic resistance may have contributed to mortality in four of these patients (three Gram negative and one Gram positive). Gram stain result had the least impact on antibiotic treatment interventions (escalation or de-escalation). Tests that improve identification time for Gram-positive pathogens and sensitivity time for Gram-negative pathogens had the greatest impact in making significant changes to antimicrobial treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

PubMed Central

López-Cortés, Luis Eduardo; Rosso-Fernández, Clara; Núñez-Núñez, María; Lavín-Alconero, Lucía; Bravo-Ferrer, José; Barriga, Ángel; Delgado, Mercedes; Lupión, Carmen; Retamar, Pilar; Rodríguez-Baño, Jesús

2017-01-01

Introduction Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. Methods and analysis The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic ‘real-practice’ trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Ethics and dissemination Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. Discussion Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. Trial registration number The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry. PMID:28601833

The broken escalator phenomenon. Aftereffect of walking onto a moving platform.

PubMed

Reynolds, R F; Bronstein, A M

2003-08-01

We investigated the physiological basis of the 'broken escalator phenomenon', namely the sensation that when walking onto an escalator which is stationary one experiences an odd sensation of imbalance, despite full awareness that the escalator is not going to move. The experimental moving surface was provided by a linear motor-powered sled, moving at 1.2 m/s. Sled velocity, trunk position, trunk angular velocity, EMG of the ankle flexors-extensors and foot-contact signals were recorded in 14 normal subjects. The experiments involved, initially, walking onto the stationary sled (condition Before). Then, subjects walked 20 times onto the moving sled (condition Moving), and it was noted that they increased their walking velocity from a baseline of 0.60 m/s to 0.90 m/s. After the moving trials, subjects were unequivocally warned that the platform would no longer move and asked to walk onto the stationary sled again (condition After). It was found that, despite this warning, subjects walked onto the stationary platform inappropriately fast (0.71 m/s), experienced a large overshoot of the trunk and displayed increased leg electromyographic (EMG) activity. Subjects were surprised by their own behaviour and subjectively reported that the 'broken escalator phenomenon', as experienced in urban life, felt similar to the experiment. By the second trial, most movement parameters had returned to baseline values. The findings represent a motor aftereffect of walking onto a moving platform that occurs despite full knowledge of the changing context. As such, it demonstrates dissociation between the declarative and procedural systems in the CNS. Since gait velocity was raised before foot-sled contact, the findings are at least partly explained by open-loop, predictive behaviour. A cautious strategy of limb stiffness was not responsible for the aftereffect, as revealed by no increase in muscle cocontraction. The observed aftereffect is unlike others previously reported in the literature, which occur only after prolonged continuous exposure to a sensory mismatch, large numbers of learning trials or unpredictable catch trials. The relative ease with which the aftereffect was induced suggests that locomotor adaptation may be more impervious to cognitive control than other types of motor learning.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

PubMed

Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

2016-06-01

Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PubMed

Belderbos, José S A; De Jaeger, Katrien; Heemsbergen, Wilma D; Seppenwoolde, Yvette; Baas, Paul; Boersma, Liesbeth J; Lebesque, Joos V

2003-02-01

To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDGmore » PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.« less

Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murthy, Vedang, E-mail: vmurthy@actrec.gov.in; Masodkar, Renuka; Kalyani, Nikhil

Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gymore » in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2]{sub 10} = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder preservation is clinically feasible, with good oncological outcomes and low rates of acute and late toxicities. Dose escalation is safe and possibly improves outcomes in bladder preservation.« less

A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam.

PubMed

Tvete, Ingunn Fride; Bjørner, Trine; Skomedal, Tor

2016-04-01

Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. © British Journal of General Practice 2016.

A de-escalation protocol for febrile neutropenia cases and its impact on carbapenem resistance: A retrospective, quasi-experimental single-center study.

PubMed

Alshukairi, Abeer; Alserehi, Haleema; El-Saed, Aiman; Kelta, Mouhammed; Rehman, Jalil U; Khan, Farrukh A; Alsalmi, Hanadi; Alattas, Majda; Aslam, Muhammad

2016-01-01

Our objective was to evaluate the impact of using an imipenem de-escalation protocol for empiric febrile neutropenia on the development of carbapenem resistance. A pre-post intervention design was used. The intervention was adopting the imipenem de-escalation approach, which began on January 1, 2012. A retrospective chart review of cases of febrile neutropenia bacteremia was performed one year before and one year after the intervention. We compared the development of carbapenem resistance between the two study periods. Seventy-five episodes of febrile neutropenia bacteremia were included in the study. They had similar demographics, clinical features and outcomes. There were 78 and 12 pathogens in the primary and follow-up blood cultures, respectively. Approximately 61% and 66% of the primary and follow-up blood cultures, respectively, were gram-negative bacteria with similar carbapenem resistance profiles in the two study periods. In our study population, 57% of the gram-negative bacteria were ESBL pathogens. The resistance of the gram-negative bacteria to piperacillin/tazobactam (72% versus 53%, p=0.161), imipenem (16% versus 11%, p=0.684), and meropenem (8% versus 16%, p=0.638) did not significantly change after our policy change. In conclusion, the use of the carbapenem de-escalation approach for febrile neutropenia in our institution was not associated with an increase in carbepenem resistance. Future prospective multi-center studies are recommended to further confirm the current findings. Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

De-escalating Antibiotic Use in the Inpatient Setting: Strategies, Controversies, and Challenges.

PubMed

Daniel Markley, J; Bernard, Shaina; Bearman, Gonzalo; Stevens, Michael P

2017-04-01

Antibiotic de-escalation (ADE) is widely accepted as an integral strategy to curtail the global antibiotic resistance crisis. However, there is significant uncertainty regarding the ideal ADE strategy and its true impact on antibiotic resistance. Rapid diagnostic testing has the potential to enhance ADE strategies. Herein, we aim to discuss the current strategies, controversies, and challenges of ADE in the inpatient setting. A consensus definition of ADE remains elusive at this time. Preliminary studies utilizing rapid diagnostic tests including matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), procalcitonin, and other molecular techniques have demonstrated the potential to support ADE strategies. In the absence of evidence-based, highly specific ADE protocols, the likelihood that individual providers will make consistent, often challenging, decisions to de-escalate antibiotic therapy is low. Antimicrobial stewardship programs should support local physicians with ADE and develop innovative ways to integrate ADE into the broader construct of antimicrobial stewardship programs. The evolving field of rapid diagnostics has significant potential to improve ADE strategies, but more research is needed to fully realize this goal.

An evaluation of three methods of saying "no" to avoid an escalating response class hierarchy.

PubMed

Mace, F Charles; Pratt, Jamie L; Prager, Kevin L; Pritchard, Duncan

2011-01-01

We evaluated the effects of three different methods of denying access to requested high-preference activities on escalating problem behavior. Functional analysis and response class hierarchy (RCH) assessment results indicated that 4 topographies of problem behaviors displayed by a 13-year-old boy with high-functioning autism constituted an RCH maintained by positive (tangible) reinforcement. Identification of the RCH comprised the baseline phase, during which computer access was denied by saying "no" and providing an explanation for the restriction. Two alternative methods of saying "no" were then evaluated. These methods included (a) denying computer access while providing an opportunity to engage in an alternative preferred activity and (b) denying immediate computer access by arranging a contingency between completion of a low-preference task and subsequent computer access. Results indicated that a hierarchy of problem behavior may be identified in the context of denying access to a preferred activity and that it may be possible to prevent occurrences of escalating problem behavior by either presenting alternative options or arranging contingencies when saying "no" to a child's requests.

A phase I study of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors potentially responsive to mitoxantrone

PubMed Central

Resta, Lee P.; Pili, Roberto; Eisenberger, Mario A.; Spitz, Avery; King, Serina; Porter, Jennifer; Franke, Amy; Boinpally, Ramesh; Sweeney, Christopher J.

2010-01-01

Purpose To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. Methods This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m2 given on Day 1 of each 21-day cycle. Results OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. Conclusion The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued. PMID:20445979

Tobacco and the Escalating Global Cancer Burden

PubMed Central

Oppeltz, Richard F.; Jatoi, Ismail

2011-01-01

The global burden of cancer is escalating as a result of dramatic increases in the use of tobacco in the developing world. The use of tobacco is linked to the development of a broad variety of cancers, mainly lung cancer, the single most common cancer in the world. Tobacco smoking-attributable deaths extends beyond cancer and include stroke, heart attack and COPD. Widening disparities in cancer-related mortality have shifted towards a more dramatic burden in the developing world. Appropriate interventions must be implemented to reduce tobacco use and prevent global mortality that has escalated to epidemic levels. Tobacco control policies, including public health advertisement campaigns, warning labels, adoption of smoke-free laws, comprehensive bans and tax policies are highly effective measures to control tobacco use. Clinicians and academic institutions have to be actively committed to support tobacco control initiatives. The reduction in cancer related morbidity and mortality should be viewed as a global crisis and definitive results will depend on a multilevel effort to effectively reduce the burden of cancer, particularly in underprivileged regions of the world. PMID:21869888

Stairs or escalator? Using theories of persuasion and motivation to facilitate healthy decision making.

PubMed

Suri, Gaurav; Sheppes, Gal; Leslie, Sara; Gross, James J

2014-12-01

To encourage an increase in daily activity, researchers have tried a variety of health-related communications, but with mixed results. In the present research-using the stair escalator choice context-we examined predictions derived from the Heuristic Systematic Model (HSM), Self Determination Theory (SDT), and related theories. Specifically, we tested whether (as predicted by HSM) signs that encourage heuristic processing ("Take the Stairs") would have greatest impact when placed at the stair/escalator point of choice (when processing time is limited), whereas signs that encourage systematic processing ("Will You Take the Stairs?") would have greatest impact when placed at some distance from the point of choice (when processing time is less limited). We also tested whether (as predicted by SDT) messages promoting autonomy would be more likely to result in sustained motivated behavior (i.e., stair taking at subsequent uncued choice points) than messages that use commands. A series of studies involving more than 9,000 pedestrians provided support for these predictions. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Increased cost of illness among European patients with type 2 diabetes treated with insulin.

PubMed

Nuhoho, Solomon; Vietri, Jeffrey; Worbes-Cerezo, Melany

2017-01-01

To investigate the association between outcomes and different escalating combinations of non-insulin medications vs. insulin. Data were taken from the 2013 5EU NHWS, a cross-sectional survey including 62,000 respondents across France, Germany, Italy, Spain, and the UK. Costs were estimated from self-reported work impairment and healthcare visits using average wages and unit costs. Respondents taking antihyperglycemic medications (n = 2894) were compared according to treatment type using unadjusted comparisons followed by regression to adjust for confounders. Insulin users had the highest costs and worse outcomes, a pattern that remained after adjustment for a range of sociodemographic and disease characteristics. Incremental direct costs were approximately €800. Incremental indirect costs, applicable only to the employed, were larger than incremental direct costs, but were statistically significant only relative to non-insulin monotherapy. Escalation using oral agents rather than insulin is associated with better quality of life and lower costs, though these relationships may not be causal. Further research is warranted on escalation using oral agents among patients for whom insulin is not required.

Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection: Comment on Coburn et al.

PubMed

Bredemeier, Markus

2018-05-09

We read with interest the study by Coburn et al. (1), a methodologically sound propensity-score matched cohort study evaluating the effect of dose escalation of allopurinol on cardiovascular (CV) and overall mortality. The results indicate that increasing doses carry a higher risk of mortality, but the authors comment that failure in achieving doses up to 600 mg may have contributed to the absence of protective effect. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Implications of the INF (intermediate nuclear force) treaty on NATO strategy. Student report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amend, J.H.

1988-03-01

The INF Treaty has refocused NATO attention on the longstanding concern of the applicability of the current NATO strategy. This study examines the implications of the INF Treaty on the current NATO strategy of Flexible Response. The tenets of Flexible Response include sustainability and escalation control. This study concludes that even prior to the INF Treaty, Flexible Response was not a valid strategy due to lack of sustainability and escalation control. In the absence of a valid Flexible Response Doctrine, NATO strategy reverts to massive Retaliation. Recommendations to alleviate this situation are suggested.

BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

PubMed Central

Bennett, Cathy; Moayyedi, Paul; Corley, Douglas A.; DeCaestecker, John; Falck-Ytter, Yngve; Falk, Gary; Vakil, Nimish; Sanders, Scott; Vieth, Michael; Inadomi, John; Aldulaimi, David; Ho, Khek-Yu; Odze, Robert; Meltzer, Stephen J.; Quigley, Eamonn; Gittens, Stuart; Watson, Peter; Zaninotto, Giovanni; Iyer, Prasad G.; Alexandre, Leo; Ang, Yeng; Callaghan, James; Harrison, Rebecca; Singh, Rajvinder; Bhandari, Pradeep; Bisschops, Raf; Geramizadeh, Bita; Kaye, Philip; Krishnadath, Sheila; Fennerty, M. Brian; Manner, Hendrik; Nason, Katie S.; Pech, Oliver; Konda, Vani; Ragunath, Krish; Rahman, Imdadur; Romero, Yvonne; Sampliner, Richard; Siersema, Peter D.; Tack, Jan; Tham, Tony C.K.; Trudgill, Nigel; Weinberg, David S.; Wang, Jean; Wang, Kenneth; Wong, Jennie Y.Y.; Attwood, Stephen; Malfertheiner, Peter; MacDonald, David; Barr, Hugh; Ferguson, Mark K.; Jankowski, Janusz

2015-01-01

OBJECTIVES Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research. PMID:25869390

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with photons and protons for non-small cell lung cancer.

PubMed

Roelofs, Erik; Engelsman, Martijn; Rasch, Coen; Persoon, Lucas; Qamhiyeh, Sima; de Ruysscher, Dirk; Verhaegen, Frank; Pijls-Johannesma, Madelon; Lambin, Philippe

2012-01-01

This multicentric in silico trial compares photon and proton radiotherapy for non-small cell lung cancer patients. The hypothesis is that proton radiotherapy decreases the dose and the volume of irradiated normal tissues even when escalating to the maximum tolerable dose of one or more of the organs at risk (OAR). Twenty-five patients, stage IA-IIIB, were prospectively included. On 4D F18-labeled fluorodeoxyglucose-positron emission tomography-computed tomography scans, the gross tumor, clinical and planning target volumes, and OAR were delineated. Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) photon and passive scattered conformal proton therapy (PSPT) plans were created to give 70 Gy to the tumor in 35 fractions. Dose (de-)escalation was performed by rescaling to the maximum tolerable dose. Protons resulted in the lowest dose to the OAR, while keeping the dose to the target at 70 Gy. The integral dose (ID) was higher for 3DCRT (59%) and IMRT (43%) than for PSPT. The mean lung dose reduced from 18.9 Gy for 3DCRT and 16.4 Gy for IMRT to 13.5 Gy for PSPT. For 10 patients, escalation to 87 Gy was possible for all 3 modalities. The mean lung dose and ID were 40 and 65% higher for photons than for protons, respectively. The treatment planning results of the Radiation Oncology Collaborative Comparison trial show a reduction of ID and the dose to the OAR when treating with protons instead of photons, even with dose escalation. This shows that PSPT is able to give a high tumor dose, while keeping the OAR dose lower than with the photon modalities.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

PubMed

Bautista, Francisco; Moreno, Lucas; Marshall, Lynley; Pearson, Andrew D J; Geoerger, Birgit; Paoletti, Xavier

2017-11-01

Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

PubMed

Huang, Alison J; Cummings, Steven R; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2016-03-01

To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

Continuous Transdermal Nitroglycerin Therapy for Menopausal Hot Flashes: A Single-Arm Dose-Escalation Trial

PubMed Central

Huang, Alison J.; Cummings, Steven R.; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2015-01-01

Objective To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Methods Peri- and postmenopausal women reporting at least 7 hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hr nitroglycerin patch applied daily without patch-free periods. Over four weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hr as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t-tests examined change in outcomes between baseline and maximal-dose therapy as well as after discontinuation of nitroglycerin. Results Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hr, three to 0.4 mg/hr, two to 0.2 mg/hr, and one remained on 0.1 mg/hr nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P=0.041) and 96% increase in moderate-to-severe hot flashes (P<0.001). Conclusions Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel non-hormonal hot flash treatment. PMID:26263283

The Role of Early Childhood ADHD and Subsequent CD in the Initiation and Escalation of Adolescent Cigarette, Alcohol, and Marijuana Use

PubMed Central

Sibley, Margaret H.; Pelham, William E.; Molina, Brooke S.G.; Coxe, Stefany; Kipp, Heidi; Gnagy, Elizabeth M.; Meinzer, Michael; Ross, J. Megan; Lahey, Benjamin B.

2014-01-01

Objective Adolescents with Attention Deficit/Hyperactivity Disorder (ADHD) are at an increased risk for substance use but the pathways through which this risk emerges are insufficiently understood. Method Tobacco, alcohol, and marijuana outcomes were compared between adolescents diagnosed with ADHD in early childhood (N=113) and demographically similar controls (N=65). Participants were assessed from age 5 until age 18. A comprehensive history of adolescent substance use was compiled for each participant and growth in ADHD and Conduct Disorder (CD) were modeled as they related to substance use outcomes. Results Results indicated that when compared to controls, adolescents with ADHD were more likely to try cigarettes, initiate alcohol use at early ages, and smoke marijuana more frequently. Furthermore, adolescents with ADHD were four to five times more likely than controls to escalate to heavy cigarette and marijuana use after trying these substances once. Adolescents with ADHD who escalated to heavy use patterns were more likely to display early cigarette use and marked problems with family members, but displayed fewer peer problems. There was evidence of baseline effects (latent intercept, measured at age five) for both ADHD and CD on substance use outcomes. Furthermore, growth in ADHD symptoms accounted for much of the growth in CD symptoms, and consequently, escalating CD symptoms in childhood (latent slope) were viewed as a mediator of the relationship between ADHD and cigarette and marijuana use. Maternal drinking in early childhood was the strongest predictor of early adolescent alcohol use. Conclusions These findings are discussed with respect to the role of ADHD in the development of adolescent risk outcomes. PMID:24886010

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Training paediatric healthcare staff in recognising, understanding and managing conflict with patients and families: findings from a survey on immediate and 6-month impact.

PubMed

Forbat, Liz; Simons, Jean; Sayer, Charlotte; Davies, Megan; Barclay, Sarah

2017-03-01

Conflict is a recognised component of healthcare. Disagreements about treatment protocols, treatment aims and poor communication are recognised warning signs. Conflict management strategies can be used to prevent escalation, but are not a routine component of clinical training. To report the findings from a novel training intervention, aimed at enabling paediatric staff to identify and understand the warning signs of conflict, and to implement conflict resolution strategies. Self-report measures were taken at baseline, immediately after the training and at 6 months. Questionnaires recorded quantitative and qualitative feedback on the experience of training, and the ability to recognise and de-escalate conflict. The training was provided in a tertiary teaching paediatric hospital in England over 18 months, commencing in June 2013. A 4-h training course on identifying, understanding and managing conflict was provided to staff. Baseline data were collected from all 711 staff trained, and 6-month follow-up data were collected for 313 of those staff (44%). The training was successful in equipping staff to recognise and de-escalate conflict. Six months after the training, 57% of respondents had experienced conflict, of whom 91% reported that the training had enabled them to de-escalate the conflict. Learning was retained at 6 months with staff more able than at baseline recognising conflict triggers (Fischer's exact test, p=0.001) and managing conflict situations (Pearson's χ 2 test, p=0.001). This training has the potential to reduce substantially the human and economic costs of conflicts for healthcare providers, healthcare staff, patients and relatives. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer☆

PubMed Central

Warren, Samantha; Partridge, Mike; Carrington, Rhys; Hurt, Chris; Crosby, Thomas; Hawkins, Maria A.

2014-01-01

Purpose This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm3. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001. Conclusions Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials. PMID:25304796

A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab.

PubMed

Velayos, Fernando S; Kahn, James G; Sandborn, William J; Feagan, Brian G

2013-06-01

Patients with Crohn's disease who become unresponsive to therapy with tumor necrosis factor antagonists are managed initially with either empiric dose escalation or testing-based strategies. The comparative cost effectiveness of these 2 strategies is unknown. We investigated whether a testing-based strategy is more cost effective than an empiric dose-escalation strategy. A decision analytic model that simulated 2 cohorts of patients with Crohn's disease compared outcomes for the 2 strategies over a 1-year time period. The incremental cost-effectiveness ratio of the empiric strategy was expressed as cost per quality-adjusted life-year (QALY) gained, compared with the testing-based strategy. We performed 1-way, probabilistic, and prespecified secondary analyses. The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). In sensitivity analyses, the incremental cost-effectiveness ratio of the empiric strategy ranged from $500,000 to more than $5 million per QALY gained. Similar rates of remission (63% vs 66%) and response (28% vs 26%) were achieved through differential use of available interventions. The testing-based strategy resulted in a higher percentage of surgeries (48% vs 34%) and lower percentage use of high-dose biological therapy (41% vs 54%). A testing-based strategy is a cost-effective alternative to the current strategy of empiric dose escalation for managing patients with Crohn's disease who have lost responsiveness to infliximab. The basis for this difference is lower cost at similar outcomes. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Intraoperative Secondary Insults During Orthopedic Surgery in Traumatic Brain Injury.

PubMed

Algarra, Nelson N; Lele, Abhijit V; Prathep, Sumidtra; Souter, Michael J; Vavilala, Monica S; Qiu, Qian; Sharma, Deepak

2017-07-01

Secondary insults worsen outcomes after traumatic brain injury (TBI). However, data on intraoperative secondary insults are sparse. The primary aim of this study was to examine the prevalence of intraoperative secondary insults during orthopedic surgery after moderate-severe TBI. We also examined the impact of intraoperative secondary insults on postoperative head computed tomographic scan, intracranial pressure (ICP), and escalation of care within 24 hours of surgery. We reviewed medical records of TBI patients 18 years and above with Glasgow Coma Scale score <13 who underwent single orthopedic surgery within 2 weeks of TBI. Secondary insults examined were: systemic hypotension (systolic blood pressure<90 mm Hg), intracranial hypertension (ICP>20 mm Hg), cerebral hypotension (cerebral perfusion pressure<50 mm Hg), hypercarbia (end-tidal CO2>40 mm Hg), hypocarbia (end-tidal CO2<30 mm Hg in absence of intracranial hypertension), hyperglycemia (glucose>200 mg/dL), hypoglycemia (glucose<60 mg/dL), and hyperthermia (temperature >38°C). A total of 78 patients (41 [18 to 81] y, 68% male) met the inclusion criteria. The most common intraoperative secondary insults were systemic hypotension (60%), intracranial hypertension and cerebral hypotension (50% and 45%, respectively, in patients with ICP monitoring), hypercarbia (32%), and hypocarbia (29%). Intraoperative secondary insults were associated with worsening of head computed tomography, postoperative decrease of Glasgow Coma Scale score by ≥2, and escalation of care. After Bonferroni correction, association between cerebral hypotension and postoperative escalation of care remained significant (P<0.001). Intraoperative secondary insults were common during orthopedic surgery in patients with TBI and were associated with postoperative escalation of care. Strategies to minimize intraoperative secondary insults are needed.

The role of early childhood ADHD and subsequent CD in the initiation and escalation of adolescent cigarette, alcohol, and marijuana use.

PubMed

Sibley, Margaret H; Pelham, William E; Molina, Brooke S G; Coxe, Stefany; Kipp, Heidi; Gnagy, Elizabeth M; Meinzer, Michael; Ross, J Megan; Lahey, Benjamin B

2014-05-01

Adolescents with attention deficit/hyperactivity disorder (ADHD) are at an increased risk for substance use but the pathways through which this risk emerges are insufficiently understood. Tobacco, alcohol, and marijuana outcomes were compared between adolescents diagnosed with ADHD in early childhood (N = 113) and demographically similar controls (N = 65). Participants were assessed from age 5 until age 18. A comprehensive history of adolescent substance use was compiled for each participant and growth in ADHD and conduct disorder (CD) were modeled as they related to substance use outcomes. Results indicated that when compared with controls, adolescents with ADHD were more likely to try cigarettes, initiate alcohol use at early ages, and smoke marijuana more frequently. Furthermore, adolescents with ADHD were 4 to 5 times more likely than controls to escalate to heavy cigarette and marijuana use after trying these substances once. Adolescents with ADHD who escalated to heavy use patterns were more likely to display early cigarette use and marked problems with family members, but displayed fewer peer problems. There was evidence of baseline effects (latent intercept, measured at age 5) for both ADHD and CD on substance use outcomes. Furthermore, growth in ADHD symptoms accounted for much of the growth in CD symptoms, and consequently, escalating CD symptoms in childhood (latent slope) were viewed as a mediator of the relationship between ADHD and cigarette and marijuana use. Maternal drinking in early childhood was the strongest predictor of early adolescent alcohol use. These findings are discussed with respect to the role of ADHD in the development of adolescent risk outcomes.

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Understanding how rapid response systems may improve safety for the acutely ill patient: learning from the frontline.

PubMed

Mackintosh, Nicola; Rainey, Helen; Sandall, Jane

2012-02-01

Rapid response systems (RRSs) have been introduced to facilitate effective 'rescue' of seriously ill patients on hospital wards. While research has demonstrated some benefit, uncertainty remains regarding impact on patient outcomes. Little is known about the relationship between social contexts and the application of the RRS. This comparative case study of the RRS within the medical services of two UK hospitals used ethnographic methods over a 12-month period in 2009, including observation (ward work and shadowing medical staff = 150 h), interviews with doctors, ward and critical care nurses, healthcare assistants, safety leads and managers (n=35), documentary review and analysis of routine data. Data were analysed using NVivo software. The RRS reduced variability in recording, recognition and response behaviour. The RRS formalised understandings of deterioration and provided a mandate for escalating care across professional and hierarchical boundaries. However, markers of deterioration not assimilated into risk scores were marginalised and it was harder for staff to escalate care without the 'objective evidence' provided by the score. Contextual features (eg, leadership, organisational culture and training) shaped implementation, utilisation and impact of the RRS. Reporting and feedback of audit data enabled learning about 'selected' escalation work on the wards. Difficulties with referral upwards and across medical boundaries were reported by junior medical staff. Locating a RRS within a pathway of care for the acutely ill patient illustrates the role of these safety strategies within the social organisation of clinical work. There is a need to broaden the focus of inquiry from detection and initiation of escalation (where the strategies are principally directed) towards team response behaviour and towards those medical response practices which to date have escaped scrutiny and monitoring.

Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications.

PubMed

Adelaiye, Remi; Ciamporcero, Eric; Miles, Kiersten Marie; Sotomayor, Paula; Bard, Jonathan; Tsompana, Maria; Conroy, Dylan; Shen, Li; Ramakrishnan, Swathi; Ku, Sheng-Yu; Orillion, Ashley; Prey, Joshua; Fetterly, Gerald; Buck, Michael; Chintala, Sreenivasulu; Bjarnason, Georg A; Pili, Roberto

2015-02-01

Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. ©2014 American Association for Cancer Research.

CRF type 1 receptor antagonism in ventral tegmental area of adolescent rats during social defeat: Prevention of escalated cocaine self-administration in adulthood and behavioral adaptations during adolescence

PubMed Central

Burke, Andrew R.; DeBold, Joseph F.; Miczek, Klaus A.

2016-01-01

Background Activation of corticotropin releasing factor type 1 receptors (CRF-R1) in the ventral tegmental area (VTA) represents a critical mechanism for social defeat to escalate cocaine self-administration in adult rats. Objective We determined the acute effect of a CRF-R1 antagonist (CP376395) microinfusion into the VTA prior to each episode of social defeat in adolescent rats and determined whether this drug treatment could prevent later escalation of cocaine taking in early adulthood. Methods Rats were implanted with bilateral cannulae aimed at the VTA five days before the first social defeat. Bilateral microinfusion of CP376395 (500ng/side) or vehicle occurred 20 min before each episode of social defeat on postnatal days (P) 35, 38, 41, and 44. Behavior was quantified on P35 and P44. On P57, rats were implanted with intra-jugular catheters, and subsequent cocaine self-administration was analyzed. Results CP376395-treated adolescent rats walked less and were attacked more slowly, but were socially investigated more than vehicle-treated adolescents. Vehicle-treated rats showed increased social and decreased non-social exploration from P35 to P44, while CP376395-treated rats did not. Socially defeated, vehicle-treated adolescents took more cocaine during a 24-hour unlimited access binge during adulthood. The latency to supine posture on P44 was inversely correlated with later cocaine self-administration during fixed and progressive ratio schedules of reinforcement and during the binge. Conclusions CP376395 treatment in adolescence blocked escalation of cocaine taking in adulthood. Episodes of social defeat stress engender neuroadaptation in CRF-R1s in the VTA that alter coping with social stress and that persist into adulthood. PMID:27251131

How organizational escalation prevention potential affects success of implementation of innovations: electronic medical records in hospitals.

PubMed

Lambooij, Mattijs S; Koster, Ferry

2016-05-20

Escalation of commitment is the tendency that (innovation) projects continue, even if it is clear that they will not be successful and/or become extremely costly. Escalation prevention potential (EPP), the capability of an organization to stop or steer implementation processes that do not meet their expectations, may prevent an organization of losing time and money on unsuccessful projects. EPP consists of a set of checks and balances incorporated in managerial practices that safeguard management against irrational (but very human) decisions and may limit the escalation of implementation projects. We study whether successful implementation of electronic medical records (EMRs) relates to EPP and investigate the organizational factors accounting for this relationship. Structural equation modelling (SEM), using questionnaire data of 427 doctors and 631 nurses who had experience with implementation and use of EMRs in hospitals, was applied to study whether formal governance and organizational culture mediate the relationship between EPP and the perceived added value of EMRs. Doctors and nurses in hospitals with more EPP report more successful implementation of EMR (in terms of perceived added value of the EMR). Formal governance mediates the relation between EPP and implementation success. We found no evidence that open or innovative culture explains the relationship between EPP and implementation success. There is a positive relationship between the level of EPP and perceived added value of EMRs. This relationship is explained by formal governance mechanisms of organizations. This means that management has a set of tangible tools to positively affect the success of innovation processes. However, it also means that management needs to be able to critically reflect on its (previous) actions and decisions and is willing to change plans if elements of EPP signal that the implementation process is hampered.

Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency.

PubMed

Wasserstein, Melissa P; Jones, Simon A; Soran, Handrean; Diaz, George A; Lippa, Natalie; Thurberg, Beth L; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F; Puga, Ana Cristina

2015-01-01

Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. Copyright © 2015. Published by Elsevier Inc.

Orthognathic surgery in the office setting.

PubMed

Farrell, Brian B; Tucker, Myron R

2014-11-01

The delivery of care by oral and maxillofacial surgeons is becoming more challenging because of escalating health care costs and limited reimbursement from insurance providers. The changing health care landscape forces surgical practices to be flexible and adaptive to change in order to remain viable. The delivery of surgical services continues to evolve as care traditionally performed in a hospital environment is now routinely achieved in an outpatient setting. Outpatient facilities can aid in controlling the perioperative costs associated with orthognathic surgery. Safe and efficient orthognathic surgery completed in the office can aid in controlling the escalation of health care costs. Copyright © 2014 Elsevier Inc. All rights reserved.

Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer.

PubMed

Timmer-Bonte, J N H; Punt, C J A; vd Heijden, H F M; van Die, C E; Bussink, J; Beijnen, J H; Huitema, A D R; Tjan-Heijnen, V C G

2008-05-01

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100mg/m(2) days 1, 3, 5 and cisplatin 80 mg/m(2) day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m(2) resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m(2). The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m(2) without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.

Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment

PubMed Central

Xue, Cong; Hong, Shaodong; Li, Ning; Feng, Weineng; Jia, Jun; Peng, Jiewen; Lin, Daren; Cao, Xiaolong; Wang, Siyang; Zhang, Weimin; Zhang, Hongyu; Dong, Wei; Zhang, Li

2015-01-01

There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment. PMID:26216071

EXTENDED ACCESS TO METHAMPHETAMINE SELF-ADMINISTRATION AFFECTS SENSORIMOTOR GATING IN RATS

PubMed Central

Hadamitzky, Martin; Markou, Athina; Kuczenski, Ronald

2010-01-01

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher-dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6-h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6-h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher-dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits. PMID:21070821

Gender differences in intimate-conflict initiation and escalation tendencies.

PubMed

Winstok, Zeev; Smadar-Dror, Ronit; Weinberg, Michael

2018-05-01

According to gender motivation theory, men are driven by a desire to enhance their status; whereas, women are motivated by a desire to reduce risk, and the behavioral expressions of those motivations are context-dependent. In order to test this theory in the context of intimate relationships, this study compared men's and women's escalatory tendencies in the initial development of intimate conflict. These tendencies were conceptualized in terms of four attributes: two attributes that represent response intention (decision and style) and two others that represent motivations for that intention (putting one's partner in his or her place and avoiding conflict). These attributes were measured in the context of five hypothetical situations. Each of those scenarios involved potential escalation of intimate conflict, following an intimate partner's aggressive verbal demand. The study involved a convenience sample of 403 male and female participants. The findings show that, in the initial steps of intimate-conflict development, women tend toward escalation more than men. The findings also show that the escalatory tendency, as conceptualized and measured using the examined scenarios, corresponds to actual behavior exhibited in the resolution of common issues in the couples' lives. These findings reinforce gender motivation theory. © 2018 Wiley Periodicals, Inc.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial.

PubMed

López-Cortés, Luis Eduardo; Rosso-Fernández, Clara; Núñez-Núñez, María; Lavín-Alconero, Lucía; Bravo-Ferrer, José; Barriga, Ángel; Delgado, Mercedes; Lupión, Carmen; Retamar, Pilar; Rodríguez-Baño, Jesús

2017-06-09

Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae . The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients.

PubMed

Veizi, I Elias; Hayek, Salim M; Narouze, Samer; Pope, Jason E; Mekhail, Nagy

2011-10-01

The purpose of this study was to examine the effect of intrathecal (IT) coadministration of bupivacaine with opioids during the initial phase of opioid titration and up to 1 year after implantation of an IT drug delivery system (IDDS). The study was designed as a retrospective study. OUTCOMES ANALYZED: The outcomes analyzed for this study were pain relief, oral opioid consumption, IT opioid, and bupivacaine dosage. METHODS AND PATIENT POPULATION: The patient population for this study were consecutively implanted patients over a period of 6 years in a tertiary single center with multiple practitioners. In this retrospective study, 126 consecutive noncancer intractable pain patients were implanted with IDDS and initiated with an IT opioid (O) as a single medication or an IT opioid and bupivacaine (O + B). Pain intensity, amount of oral opioids, dose, rate, and concentration of IT opioids and bupivacaine, and number and type of IT medication used were recorded at preimplant, implant, and at 3, 6, and 12 months postimplant. The intervention used for the study was the IT delivery device implant. Significant reduction in pain intensity was observed in both groups at 12 months postimplant (O group: baseline 7.42 ± 2.1 to 5.85 ± 2.8 [n = 72, P < 0.001]; O + B group 7.35 ± 2 to 5.03 ± 2.4 (n = 54; P < 0.001]). The combination of opioids with bupivacaine from the start of IT infusion treatment resulted in a reduced progression of opioid dose escalation in comparison to patients started with opioids (O group). The rate of increase of IT opioids in the O group at 12 months was 535 ± 180%, whereas in the O + B, the dose increase was significantly lower at 185 ± 85% (P < 0.004). In both groups, there was a statistically significant decrease in oral opioid consumption compared with preimplant doses. Concomitant initial coadministration of IT bupivacaine with opioids blunts the rate of IT opioid dose escalation during the first year after implant of an IDDS. More studies are necessary to thoroughly examine IT opioid dose escalation and the effects of addition of bupivacaine to IT opioids. Blunting IT opioid dose escalation may be a beneficial long-term effect of IT bupivacaine. Wiley Periodicals, Inc.

Learning From Trials on Radiation Dose in Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, Jeffrey, E-mail: jbradley@wustl.edu; Hu, Chen

2016-11-15

In this issue of the International Journal of Radiation Oncology • Biology • Physics, Taylor et al present a meta-analysis of published data supporting 2 findings: (1) radiation dose escalation seems to benefit patients who receive radiation alone for non-small cell lung cancer; and (2) radiation dose escalation has a detrimental effect on overall survival in the setting of concurrent chemotherapy. The latter finding is supported by data but has perplexed the oncology community. Perhaps these findings are not perplexing at all. Perhaps it is simply another lesson in the major principle in radiation oncology, to minimize radiation dose to normalmore » tissues.« less

Aggressive behaviour - prevention and management in the general practice environment.

PubMed

Sim, Moira G; Wain, Toni; Khong, Eric

2011-11-01

Aggressive behaviour is commonly encountered in the general practice setting and can often be de-escalated using good communication skills. This article provides strategies to reduce and manage early aggression in the general practice environment. Aggressive behaviour usually occurs when a person feels unfairly treated. Having a systematic approach to the problem can improve safety for both staff and patients. This includes patient centred practice, identifying and managing the early signs of aggression to prevent escalation, having a plan to seek assistance if required, setting limits using a calm respectful manner and reinforcing limits using behaviour contracts when required. The physical layout of the practice and restraint of aggressive people are beyond the scope of this article.

Predictors of workplace violence among ambulance personnel: a longitudinal study.

PubMed

van der Velden, Peter G; Bosmans, Mark W G; van der Meulen, Erik

2016-04-01

To examine predictors of repeated confrontations with workplace violence among ambulance personnel, the proportion of exposure to potentially traumatic events that are aggression-related and to what extent personnel was able to prevent escalations. Although previous research assessed the prevalences among this group, little is known about predictors, to what extent PTE's are WPV-related and their abilities to prevent escalations. A longitudinal study with a 6 months' time interval ( N  =   103). At T1 demographics, workplace violence and potentially traumatic events in the past year, mental health, personality, handling of rules, coping and social organizational stressors were assessed. Confrontations with aggression were also examined at T2. Multivariate logistic regression analyses showed that only problems with superiors independently predicted repeated verbal aggression and that only the (absence of the) ability to compromise very easily predicted repeatedly being on guard and repeatedly confronted with any form of aggression. Due to very low prevalences, we could not examine predictors of repeated confrontations with physical aggression ( N  =   5) and serious threat ( N  =   7). A large majority reported that in most workplace violence cases they could prevent further escalations. About 2% reported a potentially traumatic event in the year before T1 that was WPV related and perceived as very stressful.

Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates.

PubMed

Souza-Oliveira, Ana Carolina; Cunha, Thúlio Marquez; Passos, Liliane Barbosa da Silva; Lopes, Gustavo Camargo; Gomes, Fabiola Alves; Röder, Denise Von Dolinger de Brito

2016-01-01

Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14-70%). This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlândia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations. Copyright © 2016. Published by Elsevier Editora Ltda.

Mechanisms of contextual risk for adolescent self-injury: invalidation and conflict escalation in mother-child interactions.

PubMed

Crowell, Sheila E; Baucom, Brian R; McCauley, Elizabeth; Potapova, Natalia V; Fitelson, Martha; Barth, Heather; Smith, Cindy J; Beauchaine, Theodore P

2013-01-01

According to developmental theories of self-injury, both child characteristics and environmental contexts shape and maintain problematic behaviors. Although progress has been made toward identifying biological vulnerabilities to self-injury, mechanisms underlying psychosocial risk have received less attention. In the present study, we compared self-injuring adolescents (n = 17) with typical controls (n = 20) during a mother-child conflict discussion. Dyadic interactions were coded using both global and microanalytic systems, allowing for a highly detailed characterization of mother-child interactions. We also assessed resting state psychophysiological regulation, as indexed by respiratory sinus arrhythmia (RSA). Global coding revealed that maternal invalidation was associated with adolescent anger. Furthermore, maternal invalidation and coerciveness were both related to adolescent opposition/defiance. Results from the microanalytic system indicated that self-injuring dyads were more likely to escalate conflict, suggesting a potential mechanism through which emotion dysregulation is shaped and maintained over time. Finally, mother and teen aversiveness interacted to predict adolescent resting RSA. Low-aversive teens with highly aversive mothers had the highest RSA, whereas teens in high-high dyads showed the lowest RSA. These findings are consistent with theories that emotion invalidation and conflict escalation are possible contextual risk factors for self-injury.

Salvage low-dose-rate 125I partial prostate brachytherapy after dose-escalated external beam radiotherapy

PubMed Central

Chang, Lynn

2014-01-01

Purpose To report outcomes on 5 patients treated with salvage partial low-dose-rate (LDR) 125-iodine (125I) permanent prostate seed brachytherapy (BT) for biopsy-proven locally persistent prostate cancer, following failure of dose-escalated external beam radiotherapy (EBRT). Material and methods A retrospective review of the Fox Chase Cancer Center prostate cancer database identified five patients treated with salvage partial LDR 125I seed implant for locally persistent disease following dose-escalated EBRT to 76-84 Gy in 2 Gy per fraction equivalent. All patients had post-EBRT biopsies confirming unilateral locally persistent prostate cancer. Pre-treatment, EBRT and BT details, as well as post-treatment characteristics were documented and assessed. Results The median follow-up post-implant was 41 months. All five patients exhibited low acute genitourinary and gastrointestinal toxicities. Increased erectile dysfunction was noted in three patients. There were no biochemical failures following salvage LDR 125I seed BT to date, with a median post-salvage PSA of 0.4 ng/mL. Conclusions In carefully selected patients with local persistence of disease, partial LDR 125I permanent prostate seed implant appears to be a feasible option for salvage local therapy with an acceptable toxicity profile. Further study is needed to determine long-term results of this approach. PMID:25337135

Mechanisms of Contextual Risk for Adolescent Self-Injury: Invalidation and Conflict Escalation in Mother-Child Interactions

PubMed Central

Crowell, Sheila E.; Baucom, Brian R.; McCauley, Elizabeth; Potapova, Natalia V.; Fitelson, Martha; Barth, Heather; Smith, Cindy J.; Beauchaine, Theodore P.

2013-01-01

OBJECTIVE According to developmental theories of self-injury, both child characteristics and environmental contexts shape and maintain problematic behaviors. Although progress has been made toward identifying biological vulnerabilities to self-injury, mechanisms underlying psychosocial risk have received less attention. METHOD In the present study, we compared self-injuring adolescents (n=17) with typical controls (n=20) during a mother-child conflict discussion. Dyadic interactions were coded using both global and microanalytic systems, allowing for a highly detailed characterization of mother-child interactions. We also assessed resting state psychophysiological regulation, as indexed by respiratory sinus arrhythmia (RSA). RESULTS Global coding revealed that maternal invalidation was associated with adolescent anger. Furthermore, maternal invalidation and coerciveness were both related to adolescent opposition/defiance. Results from the microanalytic system indicated that self-injuring dyads were more likely to escalate conflict, suggesting a potential mechanism through which emotion dysregulation is shaped and maintained over time. Finally, mother and teen aversiveness interacted to predict adolescent resting RSA. Low-aversive teens with highly aversive mothers had the highest RSA, whereas teens in high-high dyads showed the lowest RSA. CONCLUSIONS These findings are consistent with theories that emotion invalidation and conflict escalation are possible contextual risk factors for self-injury. PMID:23581508

Review Article: Increasing physical activity with point-of-choice prompts--a systematic review.

PubMed

Nocon, Marc; Müller-Riemenschneider, Falk; Nitzschke, Katleen; Willich, Stefan N

2010-08-01

Stair climbing is an activity that can easily be integrated into everyday life and has positive health effects. Point-of-choice prompts are informational or motivational signs near stairs and elevators/escalators aimed at increased stair climbing. The aim of this review was to assess the effectiveness of point-of-choice prompts for the promotion of stair climbing. In a systematic search of the literature, studies that assessed the effectiveness of point-of-choice prompts to increase the rate of stair climbing in the general population were identified. No restrictions were made regarding the setting, the duration of the intervention, or the kind of message. A total of 25 studies were identified. Point-of-choice prompts were predominantly posters or stair-riser banners in public traffic stations, shopping malls or office buildings. The 25 studies reported 42 results. Of 10 results for elevator settings, only three reported a significant increase in stair climbing, whereas 28 of 32 results for escalator settings reported a significant increase in stair climbing. Overall, point-of-choice prompts are able to increase the rate of stair climbing, especially in escalator settings. In elevator settings, point-of-choice prompts seem less effective. The long-term efficacy and the most efficient message format have yet to be determined in methodologically rigorous studies.

Six-month observational study of prompted stair climbing.

PubMed

Kerr, J; Eves, F; Carroll, D

2001-11-01

Despite strong evidence that prompts at the point of choice between escalators and stairs encourage stair use, the long-term effects of stair prompts have not yet been investigated. Presented here are the results of a 6-month observational study of prompted stair climbing. Escalator and adjacent stair use were monitored in a shopping mall in the Midlands region of the United Kingdom. Participants were coded for gender, age, and ethnicity. A 2-week baseline period was followed by a 12-week intervention using motivating messages on the stair risers. Follow-up data were also collected for 2 weeks immediately after the removal of the banners and 6 weeks later. A total of 45,361 escalator/stair-choice observations were made. Stair use increased significantly during the intervention period and, when the banners were removed, remained higher than at baseline. There were also significant interactions with time across the different population groups. The full public health benefits of increasing physical activity levels can only be realized if the activity is sustained. These results demonstrate that stair-riser banners can elicit a sustained increase in stair use and, even when the banners were withdrawn, overall stair use remained higher than at baseline. Copyright 2001 American Health Foundation and Academic Press.

Multisensor benchmark data for riot control

NASA Astrophysics Data System (ADS)

Jäger, Uwe; Höpken, Marc; Dürr, Bernhard; Metzler, Jürgen; Willersinn, Dieter

2008-10-01

Quick and precise response is essential for riot squads when coping with escalating violence in crowds. Often it is just a single person, known as the leader of the gang, who instigates other people and thus is responsible of excesses. Putting this single person out of action in most cases leads to a de-escalating situation. Fostering de-escalations is one of the main tasks of crowd and riot control. To do so, extensive situation awareness is mandatory for the squads and can be promoted by technical means such as video surveillance using sensor networks. To develop software tools for situation awareness appropriate input data with well-known quality is needed. Furthermore, the developer must be able to measure algorithm performance and ongoing improvements. Last but not least, after algorithm development has finished and marketing aspects emerge, meeting of specifications must be proved. This paper describes a multisensor benchmark which exactly serves this purpose. We first define the underlying algorithm task. Then we explain details about data acquisition and sensor setup and finally we give some insight into quality measures of multisensor data. Currently, the multisensor benchmark described in this paper is applied to the development of basic algorithms for situational awareness, e.g. tracking of individuals in a crowd.

Phylogenetic trends in phenolic metabolism of milkweeds (Asclepias): evidence for escalation.

PubMed

Agrawal, Anurag A; Salminen, Juha-Pekka; Fishbein, Mark

2009-03-01

Although plant-defense theory has long predicted patterns of chemical defense across taxa, we know remarkably little about the evolution of defense, especially in the context of directional phylogenetic trends. Here we contrast the production of phenolics and cardenolides in 35 species of milkweeds (Asclepias and Gomphocarpus). Maximum-likelihood analyses of character evolution revealed three major patterns. First, consistent with the defense-escalation hypothesis, the diversification of the milkweeds was associated with a trend for increasing phenolic production; this pattern was reversed (a declining evolutionary trend) for cardenolides, toxins sequestered by specialist herbivores. Second, phylogenetically independent correlations existed among phenolic classes across species. For example, coumaric acid derivatives showed negatively correlated evolution with caffeic acid derivatives, and this was likely driven by the fact that the former are used as precursors for the latter. In contrast, coumaric acid derivatives were positively correlated with flavonoids, consistent with competition for the precursor p-coumaric acid. Finally, of the phenolic classes, only flavonoids showed correlated evolution (positive) with cardenolides, consistent with a physiological and evolutionary link between the two via malonate. Thus, this study presents a rigorous test of the defense-escalation hypothesis and a novel phylogenetic approach to understanding the long-term persistence of physiological constraints on secondary metabolism.

An update on the clinical trial of BNCT at the BMRR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, R.; Capala, J.; Chanana, A.D.

1999-09-01

Boron neutron capture therapy (BNCT) was proposed more than six decades ago. It is a binary treatment modality that requires selective delivery of a {sup 10}B-labeled compound to a tumor and slow neutron irradiation of the tumor-bearing tissues. In order to improve the penetration of the neutron beam, an epithermal neutron beam was developed at the Brookhaven Medical Research Reactor (BMRR). This epithermal neutron beam can deliver relatively high thermal neutron fluence at depth without severe skin damage. Boronophenylalanine-fructose (BPA-F), a nontoxic boron carrier, was found to preferentially accumulate in tumor cells following intravenous infusion in patients with GBM. Inmore » preclinical BNCT studies in rats bearing 9L gliosarcoma, BPA-mediated BNCT was shown to be more efficacious than photon irradiation. In 1994, improvements in the neutron beam and in the understanding of the radiobiology of BPA-mediated BNCT led to the initiation of BNCT trials for human GBM at BMRR using BPA-F and epithermal neutrons. The primary objective of the phase I/II clinical trial of BPA-mediated BNCT at BMRR is to evaluate the safety of the BPA-F-mediated BNCT using epithermal neutrons in patients with GBM at a series of escalating BNCT doses. An incidental objective is to evaluate the therapeutic effectiveness of BNCT at each dose level. For each dose escalation group, the average brain dose (ABD) is escalated, as well as the minimum tumor dose. In summary, the BNCT procedure employed in the phase I/II clinical trial of BPA-F-mediated BNCT for GBM at BNL was found to be safe in all patients. The palliation afforded by a single session of BNCT compares favorably with palliation provided by fractionated photon therapy and adjuvant chemotherapy. If no evidence of radiation-induced brain toxicity is found in the current protocol, BNCT radiation dose will be further escalated.« less

Modelling the implications of reducing smoking prevalence: the benefits of increasing the UK tobacco duty escalator to public health and economic outcomes.

PubMed

Knuchel-Takano, Andre; Hunt, Daniel; Jaccard, Abbygail; Bhimjiyani, Arti; Brown, Martin; Retat, Lise; Brown, Katrina; Hinde, Sebastian; Selvarajah, Chit; Bauld, Linda; Webber, Laura

2017-12-06

Taxing tobacco is one of the most effective ways to reduce smoking prevalence, mitigate its devastating consequential health harms and progress towards a tobacco-free society. This study modelled the health and economic impacts of increasing the existing cigarette tobacco duty escalator (TDE) in the UK from the current 2% above consumer price inflation to 5%. A two-stage modelling process was used. First, a non-linear multivariate regression model was fitted to cross-sectional smoking data, creating longitudinal projections from 2015 to 2035. Second, these projections were used to predict the future incidence, prevalence and cost of 17 smoking-related diseases using a Monte Carlo microsimulation approach. A sustained increase in the duty escalator was evaluated against a baseline of continuing historical smoking trends and the existing duty escalator. A sustained increase in the TDE is projected to reduce adult smoking prevalence to 6% in 2035, from 10% in a baseline scenario. After increasing the TDE, only 65% of female and 60% of male would-be smokers would actually be smoking in 2035. The intervention is projected to avoid around 75 200 new cases of smoking-related diseases between 2015 and 2035. In 2035 alone, £49 m in National Health Service and social care costs and £192 m in societal premature mortality and morbidity costs are projected to be avoided. Increasing the UK TDE to 5% above inflation could effectively reduce smoking prevalence, prevent diseases and avoid healthcare costs. It would deliver substantial progress towards a tobacco-free society and should be implemented by the UK Government with urgency. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Identifying seasonal and temporal trends in the pressures experienced by hospitals related to unscheduled care.

PubMed

Walker, N J; Van Woerden, H C; Kiparoglou, V; Yang, Y

2016-07-26

As part of an electronic dashboard operated by Public Health Wales, senior managers at hospitals in Wales report daily "escalation" scores which reflect management opinion on the pressure a hospital is experiencing and ability to meet ongoing demand with respect to unscheduled care. An analysis was undertaken of escalation scores returned for 18 hospitals in Wales between the years 2006 and 2014 inclusive, with a view to identifying systematic temporal patterns in pressure experienced by hospitals in relation to unscheduled care. Exploratory data analysis indicated the presence of within-year cyclicity in average daily scores over all hospitals. In order to quantify this cyclicity, a Generalised Linear Mixed Model was fitted which incorporated a trigonometric function (sine and cosine) to capture within-year change in escalation. In addition, a 7-level categorical day of the week effect was fitted as well as a 3-level categorical Christmas holiday variable based on patterns observed in exploration of the raw data. All of the main effects investigated were found to be statistically significant. Firstly, significant differences emerged in terms of overall pressure reported by individual hospitals. Furthermore, escalation scores were found to vary systematically within-year in a wave-like fashion for all hospitals (but not between hospitals) with the period of highest pressure consistently observed to occur in winter and lowest pressure in summer. In addition to this annual variation, pressure reported by hospitals was also found to be influenced by day of the week (low at weekends, high early in the working week) and especially low over the Christmas period but high immediately afterwards. Whilst unpredictable to a degree, quantifiable pressure experienced by hospitals can be anticipated according to models incorporating systematic temporal patterns. In the context of finite resources for healthcare services, these findings could optimise staffing schedules and inform resource utilisation.

Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol.

PubMed

Hwa, Lara S; Chu, Adam; Levinson, Sally A; Kayyali, Tala M; DeBold, Joseph F; Miczek, Klaus A

2011-11-01

Intermittent access (IA) to drugs of abuse, as opposed to continuous access, is hypothesized to induce a kindling-type transition from moderate to escalated use, leading to dependence. Intermittent 24-hour cycles of ethanol access and deprivation can generate high levels of voluntary ethanol drinking in rats. The current study uses C57BL/6J mice (B6) in an IA to 20% ethanol protocol to escalate ethanol drinking levels. Adult male and female B6 mice were given IA to 20% ethanol on alternating days of the week with water available ad libitum. Ethanol consumption during the initial 2 hours of access was compared with a short-term, limited access "binge" drinking procedure, similar to drinking-in-the-dark (DID). B6 mice were also assessed for ethanol dependence with handling-induced convulsion, a reliable measure of withdrawal severity. After 3 weeks, male mice given IA to ethanol achieved high stable levels of ethanol drinking in excess of 20 g/kg/24 h, reaching above 100 mg/dl blood ethanol concentrations, and showed a significantly higher ethanol preference than mice given continuous access to ethanol. Also, mice given IA drank about twice as much as DID mice in the initial 2-hour access period. B6 mice that underwent the IA protocol for longer periods of time displayed more severe signs of alcohol withdrawal. Additionally, female B6 mice were given IA to ethanol and drank significantly more than males (ca. 30 g/kg/24 h). The IA method in B6 mice is advantageous because it induces escalated, voluntary, and preferential per os ethanol intake, behavior that may mimic a cardinal feature of human alcohol dependence, though the exact nature and site of ethanol acting in the brain and blood as a result of IA has yet to be determined. Copyright © 2011 by the Research Society on Alcoholism.

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

The effect of anterior proton beams in the setting of a prostate-rectum spacer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Christodouleas, John P., E-mail: christojo@uphs.upenn.edu; Tang, Shikui; Susil, Robert C.

2013-10-01

Studies suggest that anterior beams with in vivo range verification would improve rectal dosimetry in proton therapy for prostate cancer. We investigated whether prostate-rectum spacers would enhance or diminish the benefits of anterior proton beams in these treatments. Twenty milliliters of hydrogel was injected between the prostate and rectum of a cadaver using a transperineal approach. Computed tomography (CT) and magnetic resonance (MR) images were used to generate 7 uniform scanning (US) and 7 single-field uniform dose pencil-beam scanning (PBS) plans with different beam arrangements. Pearson correlations were calculated between rectal, bladder, and femoral head dosimetric outcomes and beam arrangementmore » anterior scores, which characterize the degree to which dose is delivered anteriorly. The overall quality of each plan was compared using a virtual dose-escalation study. For US plans, rectal mean dose was inversely correlated with anterior score, but for PBS plans there was no association between rectal mean dose and anterior score. For both US and PBS plans, full bladder and empty bladder mean doses were correlated with anterior scores. For both US and PBS plans, femoral head mean doses were inversely correlated with anterior score. For US plans and a full bladder, 4 beam arrangements that included an anterior beam tied for the highest maximum prescription dose (MPD). For US plans and an empty bladder, the arrangement with 1 anterior and 2 anterior oblique beams achieved the highest MPD in the virtual dose-escalation study. The dose-escalation study did not differentiate beam arrangements for PBS. All arrangements in the dose-escalation study were limited by bladder constraints except for the arrangement with 2 posterior oblique beams. The benefits of anterior proton beams in the setting of prostate-rectum spacers appear to be proton modality dependent and may not extend to PBS.« less

Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol

PubMed Central

Hwa, Lara S.; Chu, Adam; Levinson, Sally A.; Kayyali, Tala M.; DeBold, Joseph F.; Miczek, Klaus A.

2011-01-01

Background Intermittent access to drugs of abuse, as opposed to continuous access, is hypothesized to induce a kindling-type transition from moderate to escalated use, leading to dependence. Intermittent 24-hour cycles of ethanol access and deprivation can generate high levels of voluntary ethanol drinking in rats. Methods The current study uses C57BL/6J mice (B6) in an intermittent access to 20% ethanol protocol to escalate ethanol drinking levels. Adult male and female B6 mice were given intermittent access to 20% ethanol on alternating days of the week with water available ad libitum. Ethanol consumption during the initial 2 hours of access was compared to a short term, limited access “binge” drinking procedure, similar to drinking-in-the-dark (DID). B6 mice were also assessed for ethanol dependence with handling-induced convulsion (HIC), a reliable measure of withdrawal severity. Results After 3 weeks, male mice given intermittent access to ethanol achieved high stable levels of ethanol drinking in excess of 20 g/kg/24h, reaching above 100 mg/dl BEC, and showed a significantly higher ethanol preference than mice given continuous access to ethanol. Also, mice given intermittent access drank about twice as much as DID mice in the initial 2-hour access period. B6 mice that underwent the intermittent access protocol for longer periods of time displayed more severe signs of alcohol withdrawal. Additionally, female B6 mice were given intermittent access to ethanol and drank significantly more than males (ca. 30 g/kg/24h). Discussion The intermittent access method in B6 mice is advantageous because it induces escalated, voluntary, and preferential per os ethanol intake, behavior that may mimic a cardinal feature of human alcohol dependence, though the exact nature and site of ethanol acting in the brain and blood as a result of intermittent access has yet to be determined. PMID:21631540

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk; Partridge, Mike; Carrington, Rhys

2014-10-01

Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5more » Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.« less

Twelve Months of Nightly Zolpidem Does Not Lead to Dose Escalation: A Prospective Placebo-Controlled Study

PubMed Central

Roehrs, Timothy A.; Randall, Surilla; Harris, Erica; Maan, Renee; Roth, Thomas

2011-01-01

Study Objectives: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Design: Randomized, double-blind, placebo-controlled, clinical trial. Setting: Outpatient with tri-monthly one-week, sleep laboratory assessments. Participants: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32–64 yrs old, 14 men and 19 women. Interventions: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Results: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Conclusions: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. Clinical Trial Registration: Safety and Efficacy of Chronic Hypnotic Use; # NCT01006525; http://www.clinicaltrials.gov/ Citation: Roehrs TA; Randall S; Harris E; Maan R; Roth T. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. SLEEP 2011;34(2):207–212. PMID:21286241

Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnan, Sunil, E-mail: skrishnan@mdanderson.org; Chadha, Awalpreet S.; Suh, Yelin

2016-03-15

Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume wasmore » treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.« less

The effect of anterior proton beams in the setting of a prostate-rectum spacer

PubMed Central

Christodouleas, John P.; Tang, Shikui; Susil, Robert C.; McNutt, Todd R.; Song, Danny Y.; Bekelman, Justin; Deville, Curtiland; Vapiwala, Neha; DeWeese, Theodore L.; Lu, Hsiao-Ming; Both, Stefan

2014-01-01

Studies suggest that anterior beams with in vivo range verification would improve rectal dosimetry in proton therapy for prostate cancer. We investigated whether prostate-rectum spacers would enhance or diminish the benefits of anterior proton beams in these treatments. Twenty milliliters of hydrogel was injected between the prostate and rectum of a cadaver using a transperineal approach. Computed tomography (CT) and magnetic resonance (MR) images were used to generate 7 uniform scanning (US) and 7 single-field uniform dose pencil-beam scanning (PBS) plans with different beam arrangements. Pearson correlations were calculated between rectal, bladder, and femoral head dosimetric outcomes and beam arrangement anterior scores, which characterize the degree to which dose is delivered anteriorly. The overall quality of each plan was compared using a virtual dose-escalation study. For US plans, rectal mean dose was inversely correlated with anterior score, but for PBS plans there was no association between rectal mean dose and anterior score. For both US and PBS plans, full bladder and empty bladder mean doses were correlated with anterior scores. For both US and PBS plans, femoral head mean doses were inversely correlated with anterior score. For US plans and a full bladder, 4 beam arrangements that included an anterior beam tied for the highest maximum prescription dose (MPD). For US plans and an empty bladder, the arrangement with 1 anterior and 2 anterior oblique beams achieved the highest MPD in the virtual dose-escalation study. The dose-escalation study did not differentiate beam arrangements for PBS. All arrangements in the dose-escalation study were limited by bladder constraints except for the arrangement with 2 posterior oblique beams. The benefits of anterior proton beams in the setting of prostate-rectum spacers appear to be proton modality dependent and may not extend to PBS. PMID:23578497

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

PubMed

Moore, Kathleen N; Borghaei, Hossein; O'Malley, David M; Jeong, Woondong; Seward, Shelly M; Bauer, Todd M; Perez, Raymond P; Matulonis, Ursula A; Running, Kelli L; Zhang, Xiaoyan; Ponte, Jose F; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-08-15

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. © 2017 American Cancer Society.

PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, Sean E., E-mail: semcguir@mdanderson.org; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Lee, Andrew K.

2013-01-01

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specificmore » mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.« less

SU-D-202-01: Functional Lung Avoidance and Response-Adaptive Escalation (FLARE) RT: Feasibility of a Precision Radiation Oncology Strategy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, S; Lee, E; Miyaoka, R

Purpose: NSCLC patient RT is planned without consideration of spatial heterogeneity in lung function or tumor response, which may have contributed to failed uniform dose escalation in a randomized trial. The feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [{sup 99m}Tc]MAA-SPECT/CT perfused lung while redistributing 74Gy within [{sup 18}F]FDG-PET/CT biological target volumes was assessed. Methods: Eight Stage IIB–IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain <20Gy mean lung dose (MLD). Prescriptions included 60Gy to PTV and concomitantmore » boost of 74Gy mean to biological target volumes (BTV=GTV+PET margin) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial TPS via previously reported ROI discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with VMAT, proton pencil beam scanning (PBS) with 3%-3mm robust optimization, and combination PBS (avoidance) plus VMAT (escalation). Dosimetric differences were evaluated by Friedman non-parametric paired test with multiple sampling correction. Results: PTV and normal tissue objectives were not violated in 24 FLARE RT plans. Population median of mean BTV dose was 73.7Gy (68.5–75.5Gy), mean FDG-PET peak dose was 89.7Gy (73.5–103Gy), MLD was 12.3Gy (7.5–19.6Gy), and perfused MLD was 4.8Gy (0.9–12.1Gy). VMAT achieved higher dose to the FDG-PET peak subvolume (p=0.01), while PBS delivered lower dose to lung (p<0.001). Voxelwise linear correlation between BTV dose and FDG-PET uptake was higher for VMAT (R=0.93) and PBS+VMAT (R=0.94) compared to PBS alone (R=0.89). Conclusion: FLARE RT is feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG-PET dose escalation balances target/normal tissue objective tradeoffs. These results support future testing of FLARE RT safety and efficacy within a precision radiation oncology trial. This work was supported by a Research Scholar grant from the Radiological Society of North American Research & Education Foundation.« less

Strategy of Using Intratreatment Hypoxia Imaging to Selectively and Safely Guide Radiation Dose De-escalation Concurrent With Chemotherapy for Locoregionally Advanced Human Papillomavirus–Related Oropharyngeal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Nancy, E-mail: leen2@mskcc.org; Schoder, Heiko; Beattie, Brad

Purpose: To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV{sup +}) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes. Methods and Materials: Patients with HPV{sup +} oropharyngeal carcinoma were enrolled on an institutional review board–approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment {sup 18}F-fluorodeoxyglucose and dynamic {sup 18}F-FMISOmore » (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on{sup 18}F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis–free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance. Results: Thirty-three HPV{sup +} OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on {sup 18}F-FMISO PET. The 2-year distant metastasis–free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically. Conclusions: Hypoxia is present in HPV{sup +} tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies.« less

Strategy of Using Intratreatment Hypoxia Imaging to Selectively and Safely Guide Radiation Dose De-escalation Concurrent With Chemotherapy for Locoregionally Advanced Human Papillomavirus-Related Oropharyngeal Carcinoma.

PubMed

Lee, Nancy; Schoder, Heiko; Beattie, Brad; Lanning, Ryan; Riaz, Nadeem; McBride, Sean; Katabi, Nora; Li, Duan; Yarusi, Brett; Chan, Susie; Mitrani, Lindsey; Zhang, Zhigang; Pfister, David G; Sherman, Eric; Baxi, Shrujal; Boyle, Jay; Morris, Luc G T; Ganly, Ian; Wong, Richard; Humm, John

2016-09-01

To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV(+)) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes. Patients with HPV(+) oropharyngeal carcinoma were enrolled on an institutional review board-approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment (18)F-fluorodeoxyglucose and dynamic (18)F-FMISO (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on(18)F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis-free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance. Thirty-three HPV(+) OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on (18)F-FMISO PET. The 2-year distant metastasis-free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically. Hypoxia is present in HPV(+) tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Do Sell-Side Stock Analysts Exhibit Escalation of Commitment?

PubMed Central

Milkman, Katherine L.

2010-01-01

This paper presents evidence that when an analyst makes an out-of-consensus forecast of a company’s quarterly earnings that turns out to be incorrect, she escalates her commitment to maintaining an out-of-consensus view on the company. Relative to an analyst who was close to the consensus, the out-of-consensus analyst adjusts her forecasts for the current fiscal year’s earnings less in the direction of the quarterly earnings surprise. On average, this type of updating behavior reduces forecasting accuracy, so it does not seem to reflect superior private information. Further empirical results suggest that analysts do not have financial incentives to stand by extreme stock calls in the face of contradictory evidence. Managerial and financial market implications are discussed. PMID:21516220

Escalating placenta invasiveness: repeated placenta accreta at the limit of viability

PubMed Central

Greenbaum, Shirley; Khashper, Alla; Leron, Elad; Ohana, Eric; Meirovitz, Mihai; Hershkovitz, Reli; Erez, Offer

2016-01-01

Placenta percreta is an obstetric condition in which the placenta invades through the myometrium. This is the most severe form of placenta accreta and may result in spontaneous uterine rupture, a rare complication that threatens the life of both mother and fetus. In this case report, we describe a 32-year-old woman in her fourth pregnancy, diagnosed with repeated placenta accreta, which was eventually complicated by spontaneous uterine rupture at 24 weeks’ gestation. This patient had a history of abnormal placentation in prior pregnancies and previous uterine injuries. This case demonstrates a pattern of escalating placental invasiveness, and raises questions regarding the process of abnormal placentation and the manifestation of uterine rupture in scarred uteri. PMID:27143953

Phase I study of intravenous 4-hydroxyanisole.

PubMed

Rustin, G J; Stratford, M R; Lamont, A; Bleehen, N; Philip, P A; Howells, N; Watfa, R R; Slack, J A

1992-01-01

4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 mumol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

The Temporal Effects of Divorces and Separations on Children’s Academic Achievement and Problem Behavior

PubMed Central

Arkes, Jeremy

2014-01-01

This paper provides an examination of the effects of the divorce and separation process on children’s academic achievement over time. By using child fixed effects and establishing a baseline period that is 4-or-more years prior to a family disruption, I can examine how children are affected in different periods relative to the disruption and whether any negative effects subside, persist, or escalate as time passes from the disruption. With a sample of 7-14 year olds, I find: children are affected at least 2-4 years before the disruption; reading test scores are most affected; and for Reading Comprehension, the negative effects persist and even escalate as time passes from the disruption. PMID:25580066

Growth trajectories of alcohol information processing and associations with escalation of drinking in early adolescence.

PubMed

Colder, Craig R; O'Connor, Roisin M; Read, Jennifer P; Eiden, Rina D; Lengua, Liliana J; Hawk, Larry W; Wieczorek, William F

2014-09-01

This longitudinal study provided a comprehensive examination of age-related changes in alcohol outcome expectancies, subjective evaluation of alcohol outcomes, and automatic alcohol associations in early adolescence. A community sample (52% female, 75% White/non-Hispanic) was assessed annually for 3 years (mean age at the first assessment = 11.6 years). Results from growth modeling suggested that perceived likelihood of positive outcomes increased and that subjective evaluations of these outcomes were more positive with age. Perceived likelihood of negative outcomes declined with age. Automatic alcohol associations were assessed with an Implicit Association Task (IAT), and were predominantly negative, but these negative associations weakened with age. High initial levels of perceived likelihood of positive outcomes at age 11 were associated with escalation of drinking. Perceived likelihood of negative outcomes was associated with low risk for drinking at age 11, but not with changes in drinking. Increases in positive evaluations of positive outcomes were associated with increases in alcohol use. Overall, findings suggest that at age 11, youth maintain largely negative attitudes and perceptions about alcohol, but with the transition into adolescence, there is a shift toward a more neutral or ambivalent view of alcohol. Some features of this shift are associated with escalation of drinking. Our findings point to the importance of delineating multiple aspects of alcohol information processing for extending cognitive models of alcohol use to the early stages of drinking.

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

PubMed

Bahleda, Rastislav; Grilley-Olson, Juneko E; Govindan, Ramaswamy; Barlesi, Fabrice; Greillier, Laurent; Perol, Maurice; Ray-Coquard, Isabelle; Strumberg, Dirk; Schultheis, Beate; Dy, Grace K; Zalcman, Gérard; Weiss, Glen J; Walter, Annette O; Kornacker, Martin; Rajagopalan, Prabhu; Henderson, David; Nogai, Hendrik; Ocker, Matthias; Soria, Jean-Charles

2017-06-06

To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Decline in the Quality of Family Relationships Predicts Escalation in Children’s Internalizing Symptoms from Middle to Late Childhood

PubMed Central

Kochanska, Grazyna

2015-01-01

An integration of family systems perspectives with developmental psychopathology provides a framework for examining the complex interplay between family processes and developmental trajectories of child psychopathology over time. In a community sample of 98 families, we investigated the evolution of family relationships, across multiple subsystems of the family (i.e., interparental, mother-child, father-child), and the impact of these changing family dynamics on developmental trajectories of child internalizing symptoms over 6 years, from preschool age to pre-adolescence. Parent–child relationship quality was observed during lengthy sessions, consisting of multiple naturalistic, carefully scripted contexts. Each parent completed reports about interparental relationship satisfaction and child internalizing symptoms. To the extent that mothers experienced a steeper decline in interparental relationship satisfaction over time, children developed internalizing symptoms at a faster rate. Further, symptoms escalated at a faster rate to the extent that negative mother-child relationship quality increased (more negative affect expressed by both mother and child, greater maternal power assertion) and positive mother-child relationship quality decreased (less positive affect expressed by both mother and child, less warmth and positive reciprocity). Time-lagged growth curve analyses established temporal precedence such that decline in family relationships preceded escalation in child internalizing symptoms. Results suggest that family dysfunction, across multiple subsystems, represents a driving force in the progression of child internalizing symptoms. PMID:25790794

Decline in the Quality of Family Relationships Predicts Escalation in Children's Internalizing Symptoms from Middle to Late Childhood.

PubMed

Brock, Rebecca L; Kochanska, Grazyna

2015-10-01

An integration of family systems perspectives with developmental psychopathology provides a framework for examining the complex interplay between family processes and developmental trajectories of child psychopathology over time. In a community sample of 98 families, we investigated the evolution of family relationships, across multiple subsystems of the family (i.e., interparental, mother-child, father-child), and the impact of these changing family dynamics on developmental trajectories of child internalizing symptoms over 6 years, from preschool age to pre-adolescence. Parent-child relationship quality was observed during lengthy sessions, consisting of multiple naturalistic, carefully scripted contexts. Each parent completed reports about interparental relationship satisfaction and child internalizing symptoms. To the extent that mothers experienced a steeper decline in interparental relationship satisfaction over time, children developed internalizing symptoms at a faster rate. Further, symptoms escalated at a faster rate to the extent that negative mother-child relationship quality increased (more negative affect expressed by both mother and child, greater maternal power assertion) and positive mother-child relationship quality decreased (less positive affect expressed by both mother and child, less warmth and positive reciprocity). Time-lagged growth curve analyses established temporal precedence such that decline in family relationships preceded escalation in child internalizing symptoms. Results suggest that family dysfunction, across multiple subsystems, represents a driving force in the progression of child internalizing symptoms.

Changing patterns of tumor necrosis factor inhibitor use in 9074 patients with rheumatoid arthritis.

PubMed

Yazici, Yusuf; Krasnokutsky, Svetlana; Barnes, Jaime P; Hines, Patricia L; Wang, Jason; Rosenblatt, Lisa

2009-05-01

Patients with rheumatoid arthritis (RA) commonly switch between tumor necrosis factor (TNF) inhibitors after failing to control disease activity. Much of the clinical data that support switching to a second TNF agent when one agent fails to work has come from small, short-term studies. We utilized a US insurance claims database to determine patterns of use such as dose escalation, time to discontinuation, and switching between TNF inhibitors in patients with RA. A retrospective analysis was performed using an insurance claims database in the US from 2000 to 2005. TNF inhibitor use, time to switch, dose escalation, and continuation times were analyzed in patients with RA. Nine thousand seventy-four patients with RA started TNF inhibitors during the period 2000 to 2005. Etanercept was the most commonly used TNF inhibitor; infliximab had the highest duration of continuation, about 50% at 2 years. In addition, infliximab showed higher rates of dose escalation compared to etanercept and adalimumab. For all TNF inhibitors, time to switching decreased from 2000 to 2005. TNF inhibitor use patterns changed from 2000 to 2005, with more frequent changes among the different TNF inhibitors and a shorter duration of treatment before the change. Only about 50% of TNF inhibitors are still continued at 2 years, reflecting the difference between randomized clinical trials and real-world experience.

Elevated serum adipsin may predict unsuccessful treatment for cows' milk allergy but other biomarkers do not.

PubMed

Salmivesi, Susanna; Paassilta, Marita; Huhtala, Heini; Nieminen, Riina; Moilanen, Eeva; Korppi, Matti

2018-02-01

This study evaluated whether 15 allergy, immunology or inflammatory markers predicted the long-term use of cows' milk or milk products seven years after the start of oral immunotherapy (OIT) for cows' milk allergy in children. The following laboratory parameters were measured before the OIT at Tampere University Hospital, Finland, and after the six-month escalation phase: serum total immunoglobulin (Ig) E, milk-specific IgG and IgG4, eosinophil cationic protein, eosinophil-derived neurotoxin, interleukins 4, 5, 6, 10 and 12p70 and serum adipokines adiponectin, adipsin, leptin and resistin. Follow-up data from a seven-year phone questionnaire in 2015 were available for 24 children: 14 successful and 10 unsuccessful milk users. There were no significant differences in any of the 15 markers measured at the start of the study between the subjects who later formed the successful and unsuccessful groups. At the end of the six-month escalation phase of OIT, serum adipsin was higher in the group who were unsuccessful milk users at the seven-year follow-up study. None of the 15 allergy, immunology or inflammatory markers were useful in predicting the outcome of OIT. Preliminary evidence was found that high serum adipsin after the six-month escalation phase of OIT might predict unsuccessful outcome. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Biological PET-guided adaptive radiotherapy for dose escalation in head and neck cancer: a systematic review.

PubMed

Hamming-Vrieze, Olga; Navran, Arash; Al-Mamgani, Abrahim; Vogel, Wouter V

2018-06-04

In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor. A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by i) delineation of sub-volumes suitable for adaptive re-planning, ii) in silico adaptive treatment planning or iii) treatment of patients with PET based dose escalated adaptive radiotherapy. Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT). In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.

Substance use through adolescence into early adulthood after childhood-diagnosed ADHD: findings from the MTA longitudinal study.

PubMed

Molina, Brooke S G; Howard, Andrea L; Swanson, James M; Stehli, Annamarie; Mitchell, John T; Kennedy, Traci M; Epstein, Jeffery N; Arnold, L Eugene; Hechtman, Lily; Vitiello, Benedetto; Hoza, Betsy

2018-06-01

Inconsistent findings exist regarding long-term substance use (SU) risk for children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The observational follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) provides an opportunity to assess long-term outcomes in a large, diverse sample. Five hundred forty-seven children, mean age 8.5, diagnosed with DSM-IV combined-type ADHD and 258 classmates without ADHD (local normative comparison group; LNCG) completed the Substance Use Questionnaire up to eight times from mean age 10 to mean age 25. In adulthood, weekly marijuana use (32.8% ADHD vs. 21.3% LNCG) and daily cigarette smoking (35.9% vs. 17.5%) were more prevalent in the ADHD group than the LNCG. The cumulative record also revealed more early substance users in adolescence for ADHD (57.9%) than LNCG (41.9%), including younger first use of alcohol, cigarettes, marijuana, and illicit drugs. Alcohol and nonmarijuana illicit drug use escalated slightly faster in the ADHD group in early adolescence. Early SU predicted quicker SU escalation and more SU in adulthood for both groups. Frequent SU for young adults with childhood ADHD is accompanied by greater initial exposure at a young age and slightly faster progression. Early SU prevention and screening is critical before escalation to intractable levels. © 2018 Association for Child and Adolescent Mental Health.

Repeated episodes of chronic intermittent ethanol promote insensitivity to devaluation of the reinforcing effect of ethanol

PubMed Central

Lopez, M. F.; Becker, H. C.; Chandler, L. J.

2014-01-01

Studies in animal models have shown that repeated episodes of alcohol dependence and withdrawal promote escalation of drinking that is presumably associated with alterations in the addiction neurocircuitry. Using a lithium chloride-ethanol pairing procedure to devalue the reinforcing properties of ethanol, the present study determined whether multiple cycles of chronic intermittent ethanol (CIE) exposure by vapor inhalation also alters the sensitivity of drinking behavior to the devaluation of ethanol's reinforcing effects. The effect of devaluation on operant ethanol self-administration and extinction was examined in mice prior to initiation of CIE (short drinking history) and after repeated cycles of CIE or air control exposure (long drinking history). Devaluation significantly attenuated the recovery of baseline ethanol self-administration when tested either prior to CIE or in the air-exposed controls that had experienced repeated bouts of drinking but no CIE. In contrast, in mice that had undergone repeated cycles of CIE exposure that promoted escalation of ethanol drinking, self-administration was completely resistant to the effect of devaluation. Devaluation had no effect on the time course of extinction training in either pre-CIE or post-CIE mice. Taken together, these results are consistent with the suggestion that repeated cycles of ethanol dependence and withdrawal produce escalation of ethanol self-administration that is associated with a change in sensitivity to devaluation of the reinforcing properties of ethanol. PMID:25266936

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

PubMed

Humphreys, A C; Dent, J; Rodwell, S; Crawford, S M; Joffe, J K; Bradley, C; Dodwell, D; Perren, T J

2004-06-01

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Oral 5-Aminosalicylate, Mesalamine Suppository, and Mesalamine Enema as Initial Therapy for Ulcerative Proctitis in Clinical Practice with Quality of Care Implications.

PubMed

Richter, James M; Arshi, Nabeela K; Oster, Gerry

2016-01-01

Background. Ulcerative proctitis (UP) is typically treated initially with oral 5-aminosalicylate ("5-ASA"), mesalamine suppository, or mesalamine enema ("UP Rx"). Little is known about their effectiveness in practice. Methods. Using a US health insurance database, we identified new-onset UP patients between January 1, 2005, and December 31, 2007, based on the following: (1) initiation of UP Rx; (2) endoscopy in prior 30 days resulting in diagnosis of UP; and (3) no prior encounters for ulcerative colitis or Crohn's disease. We examined the incidence of therapy escalation and total costs in relation to initial UP Rx. Results. We identified 548 patients: 327 received mesalamine suppository, 138 received oral 5-ASA, and 83 received mesalamine enema, as initial UP Rx. One-third receiving oral 5-ASA experienced therapy escalation over 12 months, 21% for both mesalamine suppository and enema. Mean cumulative total cost of UP Rx over 12 months was $1552, $996, and $986 for patients beginning therapy with oral 5-ASA, mesalamine enema, and mesalamine suppository, respectively. Contrary to expert recommendations the treatments were often not continued prophylactically. Conclusions. Treatment escalation was common, and total costs of therapy were higher, in patients who initiated treatment with oral 5-ASA. Further study is necessary to assess the significance of these observations.

Oral 5-Aminosalicylate, Mesalamine Suppository, and Mesalamine Enema as Initial Therapy for Ulcerative Proctitis in Clinical Practice with Quality of Care Implications

PubMed Central

Richter, James M.; Arshi, Nabeela K.; Oster, Gerry

2016-01-01

Background. Ulcerative proctitis (UP) is typically treated initially with oral 5-aminosalicylate (“5-ASA”), mesalamine suppository, or mesalamine enema (“UP Rx”). Little is known about their effectiveness in practice. Methods. Using a US health insurance database, we identified new-onset UP patients between January 1, 2005, and December 31, 2007, based on the following: (1) initiation of UP Rx; (2) endoscopy in prior 30 days resulting in diagnosis of UP; and (3) no prior encounters for ulcerative colitis or Crohn's disease. We examined the incidence of therapy escalation and total costs in relation to initial UP Rx. Results. We identified 548 patients: 327 received mesalamine suppository, 138 received oral 5-ASA, and 83 received mesalamine enema, as initial UP Rx. One-third receiving oral 5-ASA experienced therapy escalation over 12 months, 21% for both mesalamine suppository and enema. Mean cumulative total cost of UP Rx over 12 months was $1552, $996, and $986 for patients beginning therapy with oral 5-ASA, mesalamine enema, and mesalamine suppository, respectively. Contrary to expert recommendations the treatments were often not continued prophylactically. Conclusions. Treatment escalation was common, and total costs of therapy were higher, in patients who initiated treatment with oral 5-ASA. Further study is necessary to assess the significance of these observations. PMID:27446860

Ion Elevators and Escalators in Multilevel Structures for Lossless Ion Manipulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ibrahim, Yehia M.; Hamid, Ahmed M.; Cox, Jonathan T.

2017-01-19

We describe two approaches based upon ion ‘elevator’ and ‘escalator’ components that allow moving ions to different levels in structures for lossless ion manipulations (SLIM). Guided by ion motion simulations we designed elevator and escalator components providing essentially lossless transmission in multi-level designs based upon ion current measurements. The ion elevator design allowed ions to efficiently bridge a 4 mm gap between levels. The component was integrated in a SLIM and coupled to a QTOF mass spectrometer using an ion funnel interface to evaluate the m/z range transmitted as compared to transmission within a level (e.g. in a linear section).more » Mass spectra for singly-charged ions of m/z 600-2700 produced similar mass spectra for both elevator and straight (linear motion) components. In the ion escalator design, traveling waves (TW) were utilized to transport ions efficiently between two SLIM levels. Ion current measurements and ion mobility (IM) spectrometry analysis illustrated that ions can be transported between TW-SLIM levels with no significant loss of either ions or IM resolution. These developments provide a path for the development of multilevel designs providing e.g. much longer IM path lengths, more compact designs, and the implementation of much more complex SLIM devices in which e.g. different levels may operate at different temperatures or with different gases.« less

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Paramilitary Culture.

ERIC Educational Resources Information Center

Gibson, James William

1989-01-01

Identifies the movie, "Rambo," and "Soldier of Fortune" magazine as artifacts of "paramilitary culture." Contends that they are a social phenomenon which helps legitimate the United States government's rapid escalation of military forces. (MS)

AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials.

PubMed

Wheeler, Graham M; Sweeting, Michael J; Mander, Adrian P

2016-01-01

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities.

Parental punishment and peer victimization as developmental precursors to physical dating violence involvement among girls

PubMed Central

Hipwell, Alison E.; Stepp, Stephanie D.; Xiong, Shuangyan; Keenan, Kate; Blokland, Arjan; Loeber, Rolf

2012-01-01

The current study examined harsh punishment and peer victimization as developmental precursors to girls’ involvement in physical dating violence (PDV), and the putative mediating effect of rejection sensitivity. The sample comprised 475 African American and European American participants of the longitudinal Pittsburgh Girls Study who were dating at age 17. About 10% of girls reported significant perpetration and/or victimization of physical aggression in the relationship. Results showed that initial level and escalation in harsh punishment (between 10–13 years) and escalation in peer victimization (10–15 years) predicted PDV involvement, but this relationship was not mediated by rejection sensitivity. The results highlight the need to consider the impact of early experience of different forms of aggression on girls’ risk for PDV involvement. PMID:24591807

Evaluation and modification of exercise patterns in the natural environment.

PubMed

Brownell, K D; Stunkard, A J; Albaum, J M

1980-12-01

Using a new experimental paradigm to evaluate physical activity in the natural environment, the authors made of 45,694 observations of persons using stairs or an adjacent escalator at a shopping mall, train station, and bus terminal. In study 1, stair use more than doubled for both obese and nonobese persons during two-week periods when a colorful sign encouraging use of the stairs was positioned at the stairs/escalator choice point. In study 2, stair use remained elevated for 15 consecutive days while the sign was present, decreased during a 1-month follow-up period, and returned to baseline by 3 months. These results not only demonstrate the usefulness of this paradigm, but also suggest the strength of simple, inexpensive public health interventions to increase physical activity.

Alectinib Dose Escalation Re-induces Central Nervous System Responses in ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients Relapsing on Standard Dose Alectinib

PubMed Central

Gainor, Justin F.; Chi, Andrew S.; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S.; Brastianos, Priscilla K.; Shih, Helen A.; Shaw, Alice T.

2015-01-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in ALK-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard-dose alectinib (600 mg twice daily), but subsequently recurred with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. PMID:26845119

The power of friendship: protection against an escalating cycle of peer victimization.

PubMed

Hodges, E V; Boivin, M; Vitaro, F; Bukowski, W M

1999-01-01

This study examined 2 aspects of friendship (presence and perceived qualities of a best friend) as moderators of behavioral antecedents and outcomes of peer victimization. A total of 393 children (188 boys and 205 girls) in the 4th and 5th grades (mean age = 10 years 7 months) participated during each of 2 waves of data collection in this 1-year longitudinal study. Results indicated that teacher-reported internalizing and externalizing behaviors predicted increases in peer-reported victimization, but the relation of internalizing behaviors to increases in victimization was attenuated for children with a protective friendship. Victimization predicted increases in internalizing and externalizing behaviors but only for children without a mutual best friendship. Results highlight the importance of peer friendships in preventing an escalating cycle of peer abuse.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

PubMed

Feldman, Brian M; Rivard, Georges E; Babyn, Paul; Wu, John K M; Steele, MacGregor; Poon, Man-Chiu; Card, Robert T; Israels, Sara J; Laferriere, Nicole; Gill, Kulwant; Chan, Anthony K; Carcao, Manuel; Klaassen, Robert J; Cloutier, Stephanie; Price, Victoria E; Dover, Saunya; Blanchette, Victor S

2018-06-01

Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia. In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344. Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point during the study. Tailored frequency-escalated prophylaxis leads to very little arthropathy and very good health outcomes within the WHO-ICF domains, and only uses a moderate amount of expensive clotting factor as compared with standard prophylaxis protocols. Some sequelae of bleeding were observed in our cohort, and future studies should consider a more stringent protocol of escalation. This study was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund. Subsequent renewals were funded by Bayer. Copyright © 2018 Elsevier Ltd. All rights reserved.

Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

PubMed Central

Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam

2015-01-01

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID:25815766

Continued Benefit to Androgen Deprivation Therapy for Prostate Cancer Patients Treated With Dose-Escalated Radiation Therapy Across Multiple Definitions of High-Risk Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stenmark, Matthew H.; Blas, Kevin; Halverson, Schuyler

2011-11-15

Purpose: To analyze prognostic factors in patients with high-risk prostate cancer treated with dose-escalated external-beam radiation therapy (EBRT) and androgen deprivation (ADT). Methods and Materials: Between 1998 and 2008 at University of Michigan Medical Center, 718 men were consecutively treated with EBRT to at least 75 Gy. Seven definitions of high-risk prostate cancer, applying to 11-33% of patients, were evaluated. Biochemical failure (BF), salvage ADT use, metastatic progression, and prostate cancer-specific mortality (PCSM) were estimated by the Kaplan-Meier method and Cox proportional hazards regression. Results: Each high-risk definition was associated with increased BF (hazard ratio [HR] 2.8-3.9, p < 0.0001),more » salvage ADT use (HR 3.9-6.3, p < 0.0001), metastasis (HR 3.7-6.6, p < 0.0001), and PCSM (HR 3.7-16.2, p < 0.0001). Furthermore, an increasing number of high-risk features predicted worse outcome. Adjuvant ADT yielded significant reductions in both metastases (HR 0.19-0.38, p < 0.001) and PCSM (HR 0.38-0.50, p < 0.05) for all high-risk definitions (with the exception of clinical Stage T3-4 disease) but improved BF only for those with elevated Gleason scores (p < 0.03, HR 0.25-0.48). When treated with ADT and dose-escalated EBRT, patients with Gleason scores 8 to 10, without other high-risk features, had 8-year freedom from BF of 74%, freedom from distant metastases of 93%, and cause-specific survival of 92%, with salvage ADT used in 16% of patients. Conclusion: Adjuvant ADT results in a significant improvement in clinical progression and PCSM across multiple definitions of high-risk disease even with dose-escalated EBRT. There is a subset of patients, characterized by multiple high-risk features or the presence of Gleason Pattern 5, who remain at significant risk for metastasis and PCSM despite current treatment.« less

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

PubMed

Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

2017-10-03

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest antitumor activity in patients with MET -amplified gastric cancer.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

PubMed

Roberts, Andrew W; Davids, Matthew S; Pagel, John M; Kahl, Brad S; Puvvada, Soham D; Gerecitano, John F; Kipps, Thomas J; Anderson, Mary Ann; Brown, Jennifer R; Gressick, Lori; Wong, Shekman; Dunbar, Martin; Zhu, Ming; Desai, Monali B; Cerri, Elisa; Heitner Enschede, Sari; Humerickhouse, Rod A; Wierda, William G; Seymour, John F

2016-01-28

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, E; Yuan, F; Templeton, A

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on themore » targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.« less

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

PubMed Central

Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

2006-01-01

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen. PMID:16443948

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.

Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the targetmore » volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.« less

Impact of a Clinical Pharmacy Service on the Management of Patients in a Sickle Cell Disease Outpatient Center.

PubMed

Han, Jin; Bhat, Shubha; Gowhari, Michel; Gordeuk, Victor R; Saraf, Santosh L

2016-11-01

Ambulatory care clinical pharmacy services have expanded beyond primary care settings, but literature supporting the benefits of clinical pharmacy involvement with patients who have rare diseases such as sickle cell disease (SCD) is lacking. Hydroxyurea is the only agent approved by the U.S. Food and Drug Administration for the treatment of SCD; full benefit in controlling pain episodes and other complications is achieved through monitored escalation to a maximum tolerated dose. The primary objective of this analysis was to evaluate the impact of a newly implemented clinical pharmacy service on the management of patients with SCD. We performed a retrospective cross-sectional analysis of 385 adults with SCD who received care between January 1, 2014, and December 31, 2014, at a single Sickle Cell Outpatient Center that implemented a clinical pharmacy service in August 2013. Data were collected on hydroxyurea dose escalation, immunization completion rates, and health maintenance metrics (screening for nephropathy with microalbuminuria testing, retinopathy with annual retinal examinations, and pulmonary hypertension with echocardiography). The impact of the clinical pharmacy service on quality measurements was evaluated by using univariate and multivariate analyses. The number of pharmacist encounters, defined as a clinic visit when a clinical pharmacist interacted with a patient as documented in the medical records, was associated with an improved hydroxyurea dose escalation rate (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07-2.05, p=0.02). Immunization rates for the 23-valent pneumococcal polysaccharide vaccine, the 13-valent pneumococcal conjugate vaccine, and influenza vaccine were 66%, 47%, and 62%, respectively. The number of pharmacist encounters was associated with improved immunization completion rates (OR 1.38, 95% CI 1.17-1.62, p<0.001). Improved screening for microalbuminuria (OR 2.14, 95% CI 1.60-2.86, p<0.001) and sickle cell retinopathy (OR 1.16, 95% CI 1.00-1.35, p=0.05) were also associated with the number of pharmacist encounters. A new clinical pharmacy service implemented in managing a rare disease, SCD, was associated with an improved hydroxyurea dose escalation rate, immunization completion rates, and health maintenance metrics. © 2016 Pharmacotherapy Publications, Inc.

An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging.

PubMed

Wanet, Marie; Delor, Antoine; Hanin, François-Xavier; Ghaye, Benoît; Van Maanen, Aline; Remouchamps, Vincent; Clermont, Christian; Goossens, Samuel; Lee, John Aldo; Janssens, Guillaume; Bol, Anne; Geets, Xavier

2017-10-01

The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity. A total of 13 patients with stage II-III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTV PET ) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method. The average dose to PTV PET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis. These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity.

LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models.

PubMed

King, Christopher R

2002-01-01

Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated (192)Ir HDR brachytherapy, and (125)I and (103)Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (<70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the alpha/beta ratio is low). Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low alpha/beta ratio) as the current evidence suggests.

SU-E-J-124: 18F-FDG PET Imaging to Improve RT Treatment Outcome for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

2015-06-15

Purpose: To investigate spatial correlation between high uptake regions of pre- and 10-days-post therapy{sup 1} {sup 8}F-FDG PET in recurrent lung cancer and to evaluate the feasibility of dose escalation boosting only regions with high FDG uptake identified on baseline PET. Methods: Nineteen patients with stages II– IV inoperable lung cancer were selected. Volumes of interest (VOI) on pre-therapy FDG-PET were defined using an isocontour at ≥50% of SUVmax. VOI of pre- and post-therapy PET images were correlated for the extent of overlap. A highly optimized IMRT plan to 60 Gy prescribed to PTV defined on the planning CT wasmore » designed using clinical dose constraints for the organs at risk. A boost of 18 Gy was prescribed to the VOI defined on baseline PET. A composite plan of the total 78 Gy was compared with the base 60 Gy plan. Increases in dose to the lungs, spinal cord and heart were evaluated. IMRT boost plan was compared with proton RT and SBRT boost plans. Results: Overlap fraction of baseline PET VOI with the VOI on 10 days-post therapy PET was 0.8 (95% CI: 0.7 – 0.9). Using baseline VOI as a boosting volume, dose could be escalated to 78 Gy for 15 patients without compromising the dose constraints. For 4 patients, the dose limiting factors were V20Gy and Dmean for the total lung, and Dmax for the spinal cord. An increase of the dose to OARs correlated significantly with the relative size of the boost volume. Conclusion: VOI defined on baseline 18F-FDG PET by the SUVmax-≥50% isocontour may be a biological target volume for escalated radiation dose. Dose escalation to this volume may provide improved tumor control without breaching predefined dose constraints for OARs. The best treatment outcome may be achieved with proton RT for large targets and with SBRT for small targets.« less

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

PubMed

Biran, Noa; Rowley, Scott D; Vesole, David H; Zhang, Shijia; Donato, Michele L; Richter, Joshua; Skarbnik, Alan P; Pecora, Andrew; Siegel, David S

2016-12-01

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m 2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m 2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Castle, Katherine O., E-mail: kocastle@mdanderson.org; Hoffman, Karen E.; Levy, Lawrence B.

Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis basedmore » on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.« less

Tuning the Brake While Raising the Stake: Network Dynamics during Sequential Decision-Making.

PubMed

Meder, David; Haagensen, Brian Numelin; Hulme, Oliver; Morville, Tobias; Gelskov, Sofie; Herz, Damian Marc; Diomsina, Beata; Christensen, Mark Schram; Madsen, Kristoffer Hougaard; Siebner, Hartwig Roman

2016-05-11

When gathering valued goods, risk and reward are often coupled and escalate over time, for instance, during foraging, trading, or gambling. This escalating frame requires agents to continuously balance expectations of reward against those of risk. To address how the human brain dynamically computes these tradeoffs, we performed whole-brain fMRI while healthy young individuals engaged in a sequential gambling task. Participants were repeatedly confronted with the option to continue with throwing a die to accumulate monetary reward under escalating risk, or the alternative option to stop to bank the current balance. Within each gambling round, the accumulation of gains gradually increased reaction times for "continue" choices, indicating growing uncertainty in the decision to continue. Neural activity evoked by "continue" choices was associated with growing activity and connectivity of a cortico-subcortical "braking" network that positively scaled with the accumulated gains, including pre-supplementary motor area (pre-SMA), inferior frontal gyrus, caudate, and subthalamic nucleus (STN). The influence of the STN on continue-evoked activity in the pre-SMA was predicted by interindividual differences in risk-aversion attitudes expressed during the gambling task. Furthermore, activity in dorsal anterior cingulate cortex (ACC) reflected individual choice tendencies by showing increased activation when subjects made nondefault "continue" choices despite an increasing tendency to stop, but ACC activity did not change in proportion with subjective choice uncertainty. Together, the results implicate a key role of dorsal ACC, pre-SMA, inferior frontal gyrus, and STN in computing the trade-off between escalating reward and risk in sequential decision-making. Using a paradigm where subjects experienced increasing potential rewards coupled with increasing risk, this study addressed two unresolved questions in the field of decision-making: First, we investigated an "inhibitory" network of regions that has so far been investigated with externally cued action inhibition. In this study, we show that the dynamics in this network under increasingly risky decisions are predictive of subjects' risk attitudes. Second, we contribute to a currently ongoing debate about the anterior cingulate cortex's role in sequential foraging decisions by showing that its activity is related to making nondefault choices rather than to choice uncertainty. Copyright © 2016 Meder, Haagensen, et al.

Infrastructure resiliency : a risk-based framework

DOT National Transportation Integrated Search

2013-06-26

We are living in a world of escalating risks. Globalization and spiraling infrastructure interdependencies have created complex and interlinked systems that generate many benefits but also significant risks. High-impact disruptions whether caused...

Dealing with Trespassers.

ERIC Educational Resources Information Center

Dorn, Michael

1998-01-01

Presents expert advice on keeping violations of school trespassing from escalating into worse violations of school safety. Discusses the use of trespass-warning statements, identifying areas of danger, and whether police officers in schools are the solution. (GR)

Articulated Bus Report

DOT National Transportation Integrated Search

1982-07-01

Escalating transit deficits have led the transit industry to search for methods for improving productivity and reducing operating costs. In seeking these objectives, there has been renewed interest in the cost-saving potential of high-capacity articu...

Death from undiagnosed glioblastoma multiforme and toxic self-medication presenting with concurrent dysfunctional behavior.

PubMed

Carson, Henry J; Eilers, Stanley G

2008-08-01

We encountered a decedent with an unexpected glioblastoma multiforme. A 61-year-old retired African-American woman was found dead in her home, fully clothed in her bathtub, with a pillow under her head. At autopsy, the brain showed a glioblastoma multiforme. Toxicology showed elevated hydrocodone, propoxyphene, acetaminophen, and positive paroxetine. The presence of a brain tumor likely caused a severe headache. The use of her medications could have indicated a reaction to the escalating pain of the brain trauma, and overuse could be consistent with escalating pain or loss of rational thought processes. The present case is interesting in that it had evidence of behavioral dysfunction that could be related to the brain tumor, and death arising from the glioblastoma multiforme (cerebral hemorrhage and edema) with concurrent multiple drug intoxication.

The butterfly plant arms-race escalated by gene and genome duplications

PubMed Central

Edger, Patrick P.; Heidel-Fischer, Hanna M.; Bekaert, Michaël; Rota, Jadranka; Glöckner, Gernot; Platts, Adrian E.; Heckel, David G.; Der, Joshua P.; Wafula, Eric K.; Tang, Michelle; Hofberger, Johannes A.; Smithson, Ann; Hall, Jocelyn C.; Blanchette, Matthieu; Bureau, Thomas E.; Wright, Stephen I.; dePamphilis, Claude W.; Eric Schranz, M.; Barker, Michael S.; Conant, Gavin C.; Wahlberg, Niklas; Vogel, Heiko; Pires, J. Chris; Wheat, Christopher W.

2015-01-01

Coevolutionary interactions are thought to have spurred the evolution of key innovations and driven the diversification of much of life on Earth. However, the genetic and evolutionary basis of the innovations that facilitate such interactions remains poorly understood. We examined the coevolutionary interactions between plants (Brassicales) and butterflies (Pieridae), and uncovered evidence for an escalating evolutionary arms-race. Although gradual changes in trait complexity appear to have been facilitated by allelic turnover, key innovations are associated with gene and genome duplications. Furthermore, we show that the origins of both chemical defenses and of molecular counter adaptations were associated with shifts in diversification rates during the arms-race. These findings provide an important connection between the origins of biodiversity, coevolution, and the role of gene and genome duplications as a substrate for novel traits. PMID:26100883

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

PubMed

Vogelmeier, Claus F; Criner, Gerard J; Martínez, Fernando J; Anzueto, Antonio; Barnes, Peter J; Bourbeau, Jean; Celli, Bartolome R; Chen, Rongchang; Decramer, Marc; Fabbri, Leonardo M; Frith, Peter; Halpin, David M G; López Varela, M Victorina; Nishimura, Masaharu; Roche, Nicolás; Rodríguez-Roisin, Roberto; Sin, Don D; Singh, Dave; Stockley, Robert; Vestbo, Jørgen; Wedzicha, Jadwiga A; Agustí, Alvar

2017-03-01

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of COPD has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

A solar escalator on Mars: Self-lifting of dust layers by radiative heating

NASA Astrophysics Data System (ADS)

Daerden, F.; Whiteway, J. A.; Neary, L.; Komguem, L.; Lemmon, M. T.; Heavens, N. G.; Cantor, B. A.; Hébrard, E.; Smith, M. D.

2015-09-01

Dust layers detected in the atmosphere of Mars by the light detection and ranging (LIDAR) instrument on the Phoenix Mars mission are explained using an atmospheric general circulation model. The layers were traced back to observed dust storm activity near the edge of the north polar ice cap where simulated surface winds exceeded the threshold for dust lifting by saltation. Heating of the atmospheric dust by solar radiation caused buoyant instability and mixing across the top of the planetary boundary layer (PBL). Differential advection by wind shear created detached dust layers above the PBL that ascended due to radiative heating and arrived at the Phoenix site at heights corresponding to the LIDAR observations. The self-lifting of the dust layers is similar to the "solar escalator" mechanism for aerosol layers in the Earth's stratosphere.

The butterfly plant arms-race escalated by gene and genome duplications.

PubMed

Edger, Patrick P; Heidel-Fischer, Hanna M; Bekaert, Michaël; Rota, Jadranka; Glöckner, Gernot; Platts, Adrian E; Heckel, David G; Der, Joshua P; Wafula, Eric K; Tang, Michelle; Hofberger, Johannes A; Smithson, Ann; Hall, Jocelyn C; Blanchette, Matthieu; Bureau, Thomas E; Wright, Stephen I; dePamphilis, Claude W; Eric Schranz, M; Barker, Michael S; Conant, Gavin C; Wahlberg, Niklas; Vogel, Heiko; Pires, J Chris; Wheat, Christopher W

2015-07-07

Coevolutionary interactions are thought to have spurred the evolution of key innovations and driven the diversification of much of life on Earth. However, the genetic and evolutionary basis of the innovations that facilitate such interactions remains poorly understood. We examined the coevolutionary interactions between plants (Brassicales) and butterflies (Pieridae), and uncovered evidence for an escalating evolutionary arms-race. Although gradual changes in trait complexity appear to have been facilitated by allelic turnover, key innovations are associated with gene and genome duplications. Furthermore, we show that the origins of both chemical defenses and of molecular counter adaptations were associated with shifts in diversification rates during the arms-race. These findings provide an important connection between the origins of biodiversity, coevolution, and the role of gene and genome duplications as a substrate for novel traits.

Adolescent Pathways to Co-Occurring Problem Behavior: The Effects of Peer Delinquency and Peer Substance Use

PubMed Central

Monahan, Kathryn C.; Rhew, Isaac C.; Hawkins, J. David; Brown, Eric C.

2013-01-01

Delinquency and substance use are more likely to co-occur in adolescence compared to earlier and later developmental periods. The present study examined developmental pathways to co-occurring problem behavior from 6th-10th grade (N=2,002), testing how peer delinquency and substance use were linked to transitioning between abstaining, delinquency, substance use, and co-occurring problem behavior. Developmentally, most youth transition from abstinence to delinquent behavior, and then escalate to co-occurring problem behavior. Once co-occurring problem behavior onsets, remitting to single problem behavior or abstinence is unlikely. The impact of peers on problem behavior are domain specific when individuals transition from abstaining to a single problem behavior, but are more general with respect to escalation of and desistance from problem behavior. PMID:25506186

Global disparities in health and human rights: a critical commentary.

PubMed Central

Benatar, S R

1998-01-01

Widening disparities in health and human rights at a global level represent the dark side of progress associated with escalation of economic and military exploitation and exponential population growth in the 20th century. Even the most basic universal human rights cannot be achieved for all under these circumstances. The goal of improved population health will be similarly elusive while medical care is commodified and exploited for commercial gain in the marketplace. Recognition of the powerful forces that polarize our world and commitment to reversing them are essential for the achievement of human rights for all, for the improvement of public health, and for the peaceful progress required to protect the "rational self-interest" of the most privileged people on earth against the escalation of war, disease, and other destructive forces arising from widespread poverty and ecological degradation. PMID:9491027

UV-Green Iridescence Predicts Male Quality during Jumping Spider Contests

PubMed Central

Lim, Matthew L. M.; Li, Daiqin

2013-01-01

Animal colour signals used in intraspecies communications can generally be attributed to a composite effect of structural and pigmentary colours. Notably, the functional role of iridescent coloration that is ‘purely’ structural (i.e., absence of pigments) is poorly understood. Recent studies reveal that iridescent colorations can reliably indicate individual quality, but evidence of iridescence as a pure structural coloration indicative of male quality during contests and relating to an individual’s resource-holding potential (RHP) is lacking. In age- and size-controlled pairwise male-male contests that escalate from visual displays of aggression to more costly physical fights, we demonstrate that the ultraviolet-green iridescence of Cosmophasis umbratica predicts individual persistence and relates to RHP. Contest initiating males exhibited significantly narrower carapace band separation (i.e., relative spectral positions of UV and green hues) than non-initiators. Asymmetries in carapace and abdomen brightness influenced overall contest duration and escalation. As losers retreated upon having reached their own persistence limits in contests that escalated to physical fights, losers with narrower carapace band separation were significantly more persistence. We propose that the carapace UV-green iridescence of C. umbratica predicts individual persistence and is indicative of a male’s RHP. As the observed UV-green hues of C. umbratica are ‘pure’ optical products of a multilayer reflector system, we suggest that intrasexual variations in the optical properties of the scales’ chitin-air-chitin microstructures are responsible for the observed differences in carapace band separations. PMID:23573210

UV-green iridescence predicts male quality during jumping spider contests.

PubMed

Lim, Matthew L M; Li, Daiqin

2013-01-01

Animal colour signals used in intraspecies communications can generally be attributed to a composite effect of structural and pigmentary colours. Notably, the functional role of iridescent coloration that is 'purely' structural (i.e., absence of pigments) is poorly understood. Recent studies reveal that iridescent colorations can reliably indicate individual quality, but evidence of iridescence as a pure structural coloration indicative of male quality during contests and relating to an individual's resource-holding potential (RHP) is lacking. In age- and size-controlled pairwise male-male contests that escalate from visual displays of aggression to more costly physical fights, we demonstrate that the ultraviolet-green iridescence of Cosmophasis umbratica predicts individual persistence and relates to RHP. Contest initiating males exhibited significantly narrower carapace band separation (i.e., relative spectral positions of UV and green hues) than non-initiators. Asymmetries in carapace and abdomen brightness influenced overall contest duration and escalation. As losers retreated upon having reached their own persistence limits in contests that escalated to physical fights, losers with narrower carapace band separation were significantly more persistence. We propose that the carapace UV-green iridescence of C. umbratica predicts individual persistence and is indicative of a male's RHP. As the observed UV-green hues of C. umbratica are 'pure' optical products of a multilayer reflector system, we suggest that intrasexual variations in the optical properties of the scales' chitin-air-chitin microstructures are responsible for the observed differences in carapace band separations.

Stair Descending Exercise Using a Novel Automatic Escalator: Effects on Muscle Performance and Health-Related Parameters

PubMed Central

Paschalis, Vassilis; Theodorou, Anastasios A.; Panayiotou, George; Kyparos, Antonios; Patikas, Dimitrios; Grivas, Gerasimos V.; Nikolaidis, Michalis G.; Vrabas, Ioannis S.

2013-01-01

A novel automatic escalator was designed, constructed and used in the present investigation. The aim of the present investigation was to compare the effect of two repeated sessions of stair descending versus stair ascending exercise on muscle performance and health-related parameters in young healthy men. Twenty males participated and were randomly divided into two equal-sized groups: a stair descending group (muscle-damaging group) and a stair ascending group (non-muscle-damaging group). Each group performed two sessions of stair descending or stair ascending exercise on the automatic escalator while a three week period was elapsed between the two exercise sessions. Indices of muscle function, insulin sensitivity, blood lipid profile and redox status were assessed before and immediately after, as well as at day 2 and day 4 after both exercise sessions. It was found that the first bout of stair descending exercise caused muscle damage, induced insulin resistance and oxidative stress as well as affected positively blood lipid profile. However, after the second bout of stair descending exercise the alterations in all parameters were diminished or abolished. On the other hand, the stair ascending exercise induced only minor effects on muscle function and health-related parameters after both exercise bouts. The results of the present investigation indicate that stair descending exercise seems to be a promising way of exercise that can provoke positive effects on blood lipid profile and antioxidant status. PMID:23437093

A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor–Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study

PubMed Central

Albrecht, Mary; Mukherjee, A. Lisa; Tierney, Camlin; Morse, Gene D.; Dykes, Carrie; Klingman, Karin L.; Demeter, Lisa M.

2012-01-01

Background We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. Methods Eligible HIV-infected subjects with a screening viral load of ≥1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ≤1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. Results One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [P = .13, median (25th, 75th percentile log10 copies/mL change): −0.03 (−0.74, 0.62) with TDM and 0.11 (−2.3, 0.82) with SOC]. In subgroup analysis, patients with ≥0.69 active PIs benefited from TDM compared to those with <0.69 active PIs (P = .05). Conclusions While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity. PMID:22044856

Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences

PubMed Central

DePoy, L M; Allen, A G; Gourley, S L

2016-01-01

Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called ‘reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, ‘stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in ‘stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure. PMID:27576164

Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience.

PubMed

D'Amico, E; Patti, F; Zanghì, A; Lo Fermo, S; Chisari, C G; Zappia, M

2018-05-01

The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months.

Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) infections: are carbapenem alternatives achievable in daily practice?

PubMed

Pilmis, B; Delory, T; Groh, M; Weiss, E; Emirian, A; Lecuyer, H; Lesprit, P; Zahar, J-R

2015-10-01

To avoid the use of carbapenems, alternatives such as cephamycin, piperacillin-tazobactam, and others are suggested for the treatment of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) infections. The aim of this study was to evaluate the frequency and the feasibility of antimicrobial de-escalation for ESBL-PE-related infections. A prospective observational, bi centric cohort study was conducted. All patients with ESBL-PE infections were included. De-escalation was systematically suggested if patients were clinically stable and the isolate was susceptible to possible alternatives. Seventy-nine patients were included: 36 (45.6%) were children, 27 (34.1%) were hospitalized in intensive care units, and 37 (47%) were immunocompromised. Urinary tract infections, pneumonia, and catheter-related bloodstream infections accounted for 45.6%, 19%, and 10%, respectively, of the cohort. Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae were the three most frequent causative organisms isolated. On day 5, 47 (59.2%) of the patients were still receiving carbapenems. Antimicrobial resistance (44.7%), infection relapse (26.9%), and clinical instability (19.2%) were the most important reasons for not prescribing alternatives. E. coli-related infections appeared to be a protective factor against maintaining the carbapenem prescription (odds ratio 0.11, 95% confidence interval 0.041-0.324; p=0.0013). In clinical practice, less than 50% of patients with ESBL-PE-related infections were de-escalated after empirical treatment with carbapenems. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Male monkeys use punishment and coercion to de-escalate costly intergroup fights.

PubMed

Arseneau-Robar, T Jean M; Müller, Eliane; Taucher, Anouk L; van Schaik, Carel P; Bshary, Redouan; Willems, Erik P

2018-06-13

In numerous social species, males direct aggression towards female group members during intergroup fights, and this behaviour is commonly thought to function as mate guarding, even though males often target non-receptive females. In studying intergroup fights in a wild population of vervet monkeys, we found that male intragroup aggression was primarily directed towards individuals who had either just finished exhibiting, or were currently attempting to instigate intergroup aggression. Targeted females were less likely to instigate intergroup aggression in the future, indicating that male intragroup aggression functioned as coercion (when directed towards those who were currently trying to instigate a fight) and punishment (when directed towards those who had recently fought). These manipulative tactics effectively prevented intergroup encounters from escalating into fights and often de-escalated ongoing conflicts. Males who were likely sires were those most likely to use punishment/coercion, particularly when they were wounded, and, therefore, less able to protect vulnerable offspring should a risky intergroup fight erupt. This work, along with our previous finding that females use punishment and rewards to recruit males into participating in intergroup fights, highlights the inherent conflict of interest that exists between the sexes, as well as the role that social incentives can play in resolving this conflict. Furthermore, unlike other studies which have found punishment to be used asymmetrically between partners, these works represent a novel example of reciprocal punishment in a non-human animal. © 2018 The Author(s).

Repeated episodes of chronic intermittent ethanol promote insensitivity to devaluation of the reinforcing effect of ethanol.

PubMed

Lopez, M F; Becker, H C; Chandler, L J

2014-11-01

Studies in animal models have shown that repeated episodes of alcohol dependence and withdrawal promote escalation of drinking that is presumably associated with alterations in the addiction neurocircuitry. Using a lithium chloride-ethanol pairing procedure to devalue the reinforcing properties of ethanol, the present study determined whether multiple cycles of chronic intermittent ethanol (CIE) exposure by vapor inhalation also alters the sensitivity of drinking behavior to the devaluation of ethanol's reinforcing effects. The effect of devaluation on operant ethanol self-administration and extinction was examined in mice prior to initiation of CIE (short drinking history) and after repeated cycles of CIE or air control exposure (long drinking history). Devaluation significantly attenuated the recovery of baseline ethanol self-administration when tested either prior to CIE or in the air-exposed controls that had experienced repeated bouts of drinking but no CIE. In contrast, in mice that had undergone repeated cycles of CIE exposure that promoted escalation of ethanol drinking, self-administration was completely resistant to the effect of devaluation. Devaluation had no effect on the time course of extinction training in either pre-CIE or post-CIE mice. Taken together, these results are consistent with the suggestion that repeated cycles of ethanol dependence and withdrawal produce escalation of ethanol self-administration that is associated with a change in sensitivity to devaluation of the reinforcing properties of ethanol. Copyright © 2014 Elsevier Inc. All rights reserved.

An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease.

PubMed

Chen, Justin R; Buchmiller, Brett L; Khan, David A

2015-01-01

Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PubMed

Wang-Gillam, Andrea; Arnold, Susanne M; Bukowski, Ronald M; Rothenberg, Mace L; Cooper, Wendy; Wang, Kenneth K; Gauthier, Eric; Lockhart, A Craig

2012-02-01

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

Potential Use of {sup 18}F-fluorodeoxyglucose Positron Emission Tomography–Based Quantitative Imaging Features for Guiding Dose Escalation in Stage III Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fried, David V., E-mail: dvfried@mdanderson.org; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas; Mawlawi, Osama

2016-02-01

Purpose: To determine whether previously identified quantitative image features (QIFs) based on {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) (co-occurrence matrix energy and solidity) are able to isolate subgroups of patients who would receive a benefit or detriment from dose escalation in terms of overall survival (OS) or progression-free survival (PFS). Methods and Materials: Subgroups of a previously analyzed 225 patient cohort were generated with the use of 5-percentile increment cutoff values of disease solidity and primary tumor co-occurrence matrix energy. The subgroups were analyzed with a log-rank test to determine whether there was a difference in OS and PFS betweenmore » patients treated with 60 to 70 Gy and those receiving 74 Gy. Results: In the entire patient cohort, there was no statistical difference in terms of OS or PFS between patients receiving 74 Gy and those receiving 60 to 70 Gy. It was qualitatively observed that as disease solidity and primary co-occurrence matrix energy increased, patients receiving 74 Gy had an improved OS and PFS compared with those receiving 60 to 70 Gy. The opposite trend (detriment of receiving 74 Gy) was also observed regarding low values of disease solidity and primary co-occurrence matrix energy. Conclusions: FDG-PET–based QIFs were found to be capable of isolating subgroups of patients who received a benefit or detriment from dose escalation.« less

Apparent Motives for Aggression in the Social Context of the Bar

PubMed Central

Graham, Kathryn; Bernards, Sharon; Osgood, D. Wayne; Parks, Michael; Abbey, Antonia; Felson, Richard B.; Saltz, Robert F.; Wells, Samantha

2013-01-01

Objective Little systematic research has focused on motivations for aggression and most of the existing research is qualitative and atheoretical. This study increases existing knowledge by using the theory of coercive actions to quantify the apparent motives of individuals involved in barroom aggression. Objectives were to examine: gender differences in the use of compliance, grievance, social identity, and excitement motives; how motives change during an aggressive encounter; and the relationship of motives to aggression severity. Method We analyzed 844 narrative descriptions of aggressive incidents observed in large late-night drinking venues as part of the Safer Bars evaluation. Trained coders rated each type of motive for the 1,507 bar patrons who engaged in aggressive acts. Results Women were more likely to be motivated by compliance and grievance, many in relation to unwanted sexual overtures from men; whereas men were more likely to be motivated by social identity concerns and excitement. Aggressive acts that escalated tended to be motivated by identity or grievance, with identity motivation especially associated with more severe aggression. Conclusions A key factor in preventing serious aggression is to develop approaches that focus on addressing identity concerns in the escalation of aggression and defusing incidents involving grievance and identity motives before they escalate. In bars, this might include training staff to recognize and defuse identity motives and eliminating grievance-provoking situations such as crowd bottlenecks and poorly managed queues. Preventive interventions generally need to more directly address the role of identity motives, especially among men. PMID:24224117

Adaptive Radiation Therapy for Localized Mesothelioma with Mediastinal Metastasis Using Helical Tomotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renaud, James; Yartsev, Slav; Department of Oncology, University of Western Ontario, London, Ontario

2009-10-01

The purpose of this study was to compare 2 adaptive radiotherapy strategies with helical tomotherapy. A patient having mesothelioma with mediastinal nodes was treated using helical tomotherapy with pretreatment megavoltage CT (MVCT) imaging. Gross tumor volumes (GTVs) were outlined on every MVCT study. Two alternatives for adapting the treatment were investigated: (1) keeping the prescribed dose to the targets while reducing the dose to the OARs and (2) escalating the target dose while maintaining the original level of healthy tissue sparing. Intensity modulated radiotherapy (step-and-shoot IMRT) and 3D conformal radiotherapy (3DCRT) plans for the patient were generated and compared. Themore » primary lesion and nodal mass regressed by 16.2% and 32.5%, respectively. Adapted GTVs and reduced planning target volume (PTV) margins of 4 mm after 22 fractions decrease the planned mean lung dose by 19.4%. For dose escalation, the planned prescribed doses may be increased from 50.0 to 58.7 Gy in PTV{sub 1} and from 60.0 to 70.5 Gy in PTV{sub 2}. The step-and-shoot IMRT plan was better in sparing healthy tissue but did not provide target coverage as well as the helical tomotherapy plan. The 3DCRT plan resulted in a prohibitively high planned dose to the spinal cord. MVCT studies provide information both for setup correction and plan adaptation. Improved healthy tissue sparing and/or dose escalation can be achieved by adaptive planning.« less

Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats.

PubMed

Zlebnik, Natalie E; Anker, Justin J; Carroll, Marilyn E

2012-12-01

Concurrent access to an exercise wheel decreases cocaine self-administration under short access (5 h/day for 5 days) conditions and suppresses cocaine-primed reinstatement in adult rats. The effect of exercise (wheel running) on the escalation of cocaine intake during long access (LgA, 6 h/day for 26 days) conditions was evaluated. Adolescent and adult female rats acquired wheel running, and behavior was allowed to stabilize for 3 days. They were then implanted with an iv catheter and allowed to self-administer cocaine (0.4 mg/kg, iv) during 6-h daily sessions for 16 days with concurrent access to either an unlocked or a locked running wheel. Subsequently, for ten additional sessions, wheel access conditions during cocaine self-administration sessions were reversed (i.e., locked wheels became unlocked and vice versa). In the adolescents, concurrent access to the unlocked exercise wheel decreased responding for cocaine and attenuated escalation of cocaine intake irrespective of whether the locked or unlocked condition came first. However, cocaine intake increased when the wheel was subsequently locked for the adolescents that had initial access to an unlocked wheel. Concurrent wheel access either before or after the locked wheel access did not reduce cocaine intake in adults. Wheel running reduced cocaine intake during LgA conditions in adolescent but not adult rats, and concurrent access to the running wheel was necessary. These results suggest that exercise prevents cocaine seeking and that this effect is more pronounced in adolescents than adults.

Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study.

PubMed

Taher, Ali T; Cappellini, M Domenica; Aydinok, Yesim; Porter, John B; Karakas, Zeynep; Viprakasit, Vip; Siritanaratkul, Noppadol; Kattamis, Antonis; Wang, Candace; Zhu, Zewen; Joaquin, Victor; Uwamahoro, Marie José; Lai, Yong-Rong

2016-03-01

Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, -6.68±7.02mg Fe/g dw [95% CI: -7.91, -5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen.

PubMed

Henke, Lauren; Kashani, Rojano; Robinson, Clifford; Curcuru, Austen; DeWees, Todd; Bradley, Jeffrey; Green, Olga; Michalski, Jeff; Mutic, Sasa; Parikh, Parag; Olsen, Jeffrey

2018-03-01

SBRT is used to treat oligometastatic or unresectable primary abdominal malignancies, although ablative dose delivery is limited by proximity of organs-at-risk (OAR). Stereotactic, magnetic resonance (MR)-guided online-adaptive radiotherapy (SMART) may improve SBRT's therapeutic ratio. This prospective Phase I trial assessed feasibility and potential advantages of SMART to treat abdominal malignancies. Twenty patients with oligometastatic or unresectable primary liver (n = 10) and non-liver (n = 10) abdominal malignancies underwent SMART. Initial plans prescribed 50 Gy/5 fractions (BED 100 Gy) with goal 95% PTV coverage by 95% of prescription, subject to hard OAR constraints. Daily real-time online-adaptive plans were created as needed, based on daily setup MR-image-set tumor/OAR "anatomy-of-the-day" to preserve hard OAR constraints, escalate PTV dose, or both. Treatment times, patient outcomes, and dosimetric comparisons between initial and adaptive plans were prospectively recorded. Online adaptive plans were created at time of treatment for 81/97 fractions, due to initial plan violation of OAR constraints (61/97) or observed opportunity for PTV dose escalation (20/97). Plan adaptation increased PTV coverage in 64/97 fractions. Zero Grade ≥ 3 acute (<6 months) treatment-related toxicities were observed. SMART is clinically deliverable and safe, allowing PTV dose escalation and/or simultaneous OAR sparing compared to non-adaptive abdominal SBRT. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Development of Economic Factors in Tunnel Construction

DOT National Transportation Integrated Search

1977-12-01

The escalating cost of underground construction of urban transportation systems has made transit planning, especially construction cost estimating, difficult. This is a study of the cost of construction of underground, rapid transit tunnels in soft g...

A Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Cancer Indications

ClinicalTrials.gov

2018-01-16

Colorectal Cancer (CRC); Ovarian Cancer (Epithelial and Fallopian Tube ); Urothelial Carcinoma; Triple-negative Breast Cancer (TNBC); Pancreatic Cancer; Acute Myeloid Leukemia/Myelodysplastic Syndrome; Multiple Myeloma (MM)

Asset management as a strategic decision-making tool in DelDOT.

DOT National Transportation Integrated Search

2008-10-01

Asset management has been receiving greater attention at both the state and national : levels. Escalating demands by the public for increased accountability, aging : infrastructure, increasingly constrained resources, new funding challenges, and incr...

Thousands show their solidarity in the battle to save bursaries.

PubMed

Longhurst, Chris

2016-01-13

Crowds of protesters who marched on Downing Street have vowed to escalate their campaign against the threat to bursaries by walking out for an hour during one of the forthcoming junior doctors' strikes.

Conflict Resolution Communications.

ERIC Educational Resources Information Center

Lincoln, Melinda G.

2002-01-01

Suggests that, due to escalating violence in contemporary society, community colleges should offer certificate or degree programs in conflict resolution. Describes a conflict resolution communication program, which teaches communication skills, mediation processes, and coping strategies to prospective mediators. (NB)

The 2011 mileage-based user fee symposium.

DOT National Transportation Integrated Search

2011-09-01

"The fuel tax is rapidly losing its ability to support system needs. Federal environmental : regulations and the escalating price of fossil fuels have created a strong incentive to develop and : utilize more fuel-efficient vehicles, which will drive ...

41 CFR 301-11.300 - When is actual expense reimbursement warranted?

Code of Federal Regulations, 2010 CFR

2010-07-01

... meals are procured at a prearranged place such as a hotel where a meeting, conference or training session is held; (b) Costs have escalated because of special events (e.g., missile launching periods...

Natural Attenuation of the Persistent Chemical Warfare Agent ...

EPA Pesticide Factsheets

Report This project studied the influence of temperature on the natural attenuation of VX from five types of porous/permeable materials: unsealed concrete, plywood, rubber escalator handrail, high density polyethylene (HDPE) plastic, and acoustic ceiling tile.

CLASSIFYING COASTAL WATERS:CURRENT NECESSITY AND HISTORICAL PERSPECTIVE

EPA Science Inventory

Coastal ecosystems are ecologically and commercially valuable, productive habitats that are experiencing escalating compromises of their structural and functional integrity. The Clean Water Act (USC 1972) requires identification of impaired water bodies and determination of the c...

Development of an analytical framework to rank pedestrian and cyclist projects.

DOT National Transportation Integrated Search

2015-10-01

Worsening traffic congestion and air pollution, rising road maintenance and construction costs, and escalating health risks from obesity to cardiovascular disease are among major motives triggering the attention of transportation authorities to walki...

Age related changes in cognitive response style in the driving task : part II.

DOT National Transportation Integrated Search

2013-05-01

This project further explored the patterns in drivers physiological arousal to periods of heightened : cognitive workload. Various physiological measures have been well established to increase with : escalating cognitive workload (Backs & Seljos, ...

GEOSPATIAL DATA ACCURACY ASSESSMENT

EPA Science Inventory

The development of robust accuracy assessment methods for the validation of spatial data represent's a difficult scientific challenge for the geospatial science community. The importance and timeliness of this issue is related directly to the dramatic escalation in the developmen...

Bed bugs, public health, and social justice: Part 2, An opinion survey.

PubMed

Eddy, Christopher; Jones, Susan C

2011-04-01

Bed bug infestations have resurged globally, nationally, and locally, yet the public health community in the U.S. has yet to mount a coordinated response to the escalating bed bug problem. Surveys of attendees at the 2009 National Environmental Health Association Annual Educational Conference & Exhibition, 2009 Ohio Association of Health Commissioners Fall Conference, 2009 Central Ohio Bed Bug Summit, and 2010 Hamilton County Council on Aging Annual Conference were conducted to gauge opinions about bed bugs. Survey results revealed that 90% of all respondents considered bed bugs to be a public health concern, and 73% indicated that bed bugs pose an environmental justice concern. These findings, which indicate that bed bugs are an inescapable public health mandate with environmental justice undertones, should rally public health agencies at federal, state, and local levels to respond with authority of agency to the escalating bed bug problem.

How to distinguish between 'business as usual' and 'significant business disruptions' and plan accordingly.

PubMed

Halliwell, Peter

2008-01-01

This paper seeks to provide an insight into Air New Zealand and how business continuity is managed in an industry with inherent disruptions. The differences between 'business as usual' and 'significant business disruptions' are outlined along with their associated criteria, response and escalation processes. The paper describes why the company incorporates the four 'R's of the Civil Defence Emergency Management Act within its BCM framework and how this aids resilience. A case study is provided that details a 'significant disruption' that occurred in November 2006. This event resulted in the total loss of a sales office and cargo shed after unrest in the Kingdom of Tonga escalated to widespread rioting, looting and destruction of their central business district. The lessons from this event have been captured and provide some essential mitigation measures that will assist in future events.

Economic evaluation of the Annual Cycle Energy System (ACES). Volume 1: Executive summary

NASA Astrophysics Data System (ADS)

1980-05-01

Three different classes of building are investigated, namely: single family residence; multifamily residence; and commercial office building. For each building type in each geographic location, the economic evaluation of the annual cycle energy system (ACES) is based on a comparison of the present worth of the ACES to the present worth of a number of conventional systems. The results of this analysis indicate that the economic viability of the ACES is very sensitive to the assumed value of the property tax, maintenance cost, and fuel escalation rates, while it is relatively insensitive to the assumed values of other parameters. Fortunately, any conceivable change in the fuel escalation rates would tend to increase the viability of the ACES concept. An increase in the assumed value of the maintenance cost or property tax would tend to make the ACES concept less viable; a decrease in either would tend to make the ACES concept more viable.

Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers.

PubMed

Zhou, Yinghui; Whitehead, John; Korhonen, Pasi; Mustonen, Mika

2008-03-01

Bayesian decision procedures have recently been developed for dose escalation in phase I clinical trials concerning pharmacokinetic responses observed in healthy volunteers. This article describes how that general methodology was extended and evaluated for implementation in a specific phase I trial of a novel compound. At the time of writing, the study is ongoing, and it will be some time before the sponsor will wish to put the results into the public domain. This article is an account of how the study was designed in a way that should prove to be safe, accurate, and efficient whatever the true nature of the compound. The study involves the observation of two pharmacokinetic endpoints relating to the plasma concentration of the compound itself and of a metabolite as well as a safety endpoint relating to the occurrence of adverse events. Construction of the design and its evaluation via simulation are presented.

Pelvic Nodal Radiotherapy in Patients With Unfavorable Intermediate and High-Risk Prostate Cancer: Evidence, Rationale, and Future Directions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morikawa, Lisa K.; Memorial Sloan-Kettering Cancer Center; Roach, Mack, E-mail: mroach@radonc.ucsf.ed

2011-05-01

Over the past 15 years, there have been three major advances in the use of external beam radiotherapy in the management of men with clinically localized prostate made. They include: (1) image guided (IG) three-dimensional conformal/intensity modulated radiotherapy; (2) radiation dose escalation; and (3) androgen deprivation therapy. To date only the last of these three advances have been shown to improve overall survival. The presence of occult pelvic nodal involvement could explain the failure of increased conformality and dose escalation to prolong survival, because the men who appear to be at the greatest risk of death from clinically localized prostatemore » cancer are those who are likely to have lymph node metastases. This review discusses the evidence for prophylactic pelvic nodal radiotherapy, including the key trials and controversies surrounding this issue.« less

An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1.

PubMed

Dutton, Julie L; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H

2016-12-01

This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.

Macroevolutionary chemical escalation in an ancient plant-herbivore arms race.

PubMed

Becerra, Judith X; Noge, Koji; Venable, D Lawrence

2009-10-27

A central paradigm in the field of plant-herbivore interactions is that the diversity and complexity of secondary compounds in plants have intensified over evolutionary time, resulting in the great variety of secondary products that currently exists. Unfortunately, testing of this proposal has been very limited. We analyzed the volatile chemistry of 70 species of the tropical plant genus Bursera and used a molecular phylogeny to test whether the species' chemical diversity or complexity have escalated. The results confirm that as new species diverged over time they tended to be armed not only with more compounds/species, but also with compounds that could potentially be more difficult for herbivores to adapt to because they belong to an increasing variety of chemical pathways. Overall chemical diversity in the genus also increased, but not as fast as species diversity, possibly because of allopatric species gaining improved defense with compounds that are new locally, but already in existence elsewhere.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

PubMed

Vogelmeier, Claus F; Criner, Gerard J; Martinez, Fernando J; Anzueto, Antonio; Barnes, Peter J; Bourbeau, Jean; Celli, Bartolome R; Chen, Rongchang; Decramer, Marc; Fabbri, Leonardo M; Frith, Peter; Halpin, David M G; López Varela, M Victorina; Nishimura, Masaharu; Roche, Nicolas; Rodriguez-Roisin, Roberto; Sin, Don D; Singh, Dave; Stockley, Robert; Vestbo, Jørgen; Wedzicha, Jadwiga A; Agusti, Alvar

2017-03-01

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed. Copyright ©2017 the American Thoracic Society. Published with permission from the American Thoracic Society. Design and branding are copyright ©ERS 2017.

Metallographic assessment of Al-12Si high-pressure die casting escalator steps.

PubMed

Vander Voort, George Frederic; Suárez-Peña, Beatriz; Asensio-Lozano, Juan

2014-10-01

A microstructural characterization study was performed on high-pressure die cast specimens extracted from escalator steps manufactured from an Al-12 wt.% Si alloy designed for structural applications. Black and white, color light optical imaging and scanning electron microscopy techniques were used to conduct the microstructural analysis. Most regions in the samples studied contained globular-rosette primary α-Al grains surrounded by an Al-Si eutectic aggregate, while primary dendritic α-Al grains were present in the surface layer. This dendritic microstructure was observed in the regions where the melt did not impinge directly on the die surface during cavity filling. Consequently, microstructures in the surface layer were nonuniform. Utilizing physical metallurgy principles, these results were analyzed in terms of the applied pressure and filling velocity during high-pressure die casting. The effects of these parameters on solidification at different locations of the casting are discussed.

Backprojection of volcanic tremor

USGS Publications Warehouse

Haney, Matthew M.

2014-01-01

Backprojection has become a powerful tool for imaging the rupture process of global earthquakes. We demonstrate the ability of backprojection to illuminate and track volcanic sources as well. We apply the method to the seismic network from Okmok Volcano, Alaska, at the time of an escalation in tremor during the 2008 eruption. Although we are able to focus the wavefield close to the location of the active cone, the network array response lacks sufficient resolution to reveal kilometer-scale changes in tremor location. By deconvolving the response in successive backprojection images, we enhance resolution and find that the tremor source moved toward an intracaldera lake prior to its escalation. The increased tremor therefore resulted from magma-water interaction, in agreement with the overall phreatomagmatic character of the eruption. Imaging of eruption tremor shows that time reversal methods, such as backprojection, can provide new insights into the temporal evolution of volcanic sources.

A longitudinal investigation of stress spillover in marriage: does spousal support adequacy buffer the effects?

PubMed

Brock, Rebecca L; Lawrence, Erika

2008-02-01

Stress spillover in marriage was examined within a stress-buffering conceptual framework in a multiwave, longitudinal sample of newlywed husbands and wives (N = 101 couples). Spousal support, chronic role strain, and marital satisfaction were assessed 4 times over 3 years and analyzed via actor-partner interdependence model and growth curve analytic techniques. Greater escalation in husbands' role strain over the first 3 years of marriage was associated with steeper declines in their marital satisfaction regardless of the adequacy of spousal support provided by their wives. In contrast, greater escalation in husbands' and wives' role strain was associated with significantly less marital decline for wives, and these links were bolstered when husbands provided wives with more adequate support. The present study is one of the first to explicate the underlying processes through which role strain and spousal support facilitate and mitigate the developmental course of marital satisfaction.

A Longitudinal Investigation of Stress Spillover in Marriage: Does Spousal Support Adequacy Buffer the Effects?

PubMed Central

Brock, Rebecca L.; Lawrence, Erika

2008-01-01

Stress spillover in marriage was examined within a stress-buffering conceptual framework in a multiwave, longitudinal sample of newlywed husbands and wives (N = 101 couples). Spousal support, chronic role strain, and marital satisfaction were assessed 4 times over 3 years and analyzed via actor–partner interdependence model and growth curve analytic techniques. Greater escalation in husbands’ role strain over the first 3 years of marriage was associated with steeper declines in their marital satisfaction regardless of the adequacy of spousal support provided by their wives. In contrast, greater escalation in husbands’ and wives’ role strain was associated with significantly less marital decline for wives, and these links were bolstered when husbands provided wives with more adequate support. The present study is one of the first to explicate the underlying processes through which role strain and spousal support facilitate and mitigate the developmental course of marital satisfaction. PMID:18266528

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

PubMed

Gainor, Justin F; Chi, Andrew S; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S; Brastianos, Priscilla K; Shih, Helen A; Shaw, Alice T

2016-02-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Liquid hydrogen production and economics for NASA Kennedy Space Center

NASA Astrophysics Data System (ADS)

Block, D. L.

1985-12-01

Detailed economic analyses for the production of liquid hydrogen used to power the Space Shuttle are presented. The hydrogen production and energy needs of the NASA Kennedy Space Center are reviewed, and steam reformation, polygeneration, and electrolysis for liquid hydrogen production are examined on an equal economic basis. The use of photovoltaics as an electrolysis power source is considered. The 1985 present worth is calculated based on life cycle costs over a 21-year period beginning with full operation in 1990. Two different sets of escalation, inflation, and discount rates are used, with revenue credit being given for energy or other products of the hydrogen production process. The results show that the economic analyses are very dependent on the escalation rates used. The least net present value is found for steam reformation of natural gas, while the best net present value is found for the electrolysis process which includes the phasing of photovoltaics.

An Update on CRF Mechanisms Underlying Alcohol Use Disorders and Dependence

PubMed Central

Quadros, Isabel Marian Hartmann; Macedo, Giovana Camila; Domingues, Liz Paola; Favoretto, Cristiane Aparecida

2016-01-01

Alcohol is the most commonly used and abused substance worldwide. The emergence of alcohol use disorders, and alcohol dependence in particular, is accompanied by functional changes in brain reward and stress systems, which contribute to escalated alcohol drinking and seeking. Corticotropin-releasing factor (CRF) systems have been critically implied in the transition toward problematic alcohol drinking and alcohol dependence. This review will discuss how dysregulation of CRF function contributes to the vulnerability for escalated alcohol drinking and other consequences of alcohol consumption, based on preclinical evidence. CRF signaling, mostly via CRF1 receptors, seems to be particularly important in conditions of excessive alcohol taking and seeking, including during early and protracted withdrawal, relapse, as well as during withdrawal-induced anxiety and escalated aggression promoted by alcohol. Modulation of CRF1 function seems to exert a less prominent role over low to moderate alcohol intake, or to species-typical behaviors. While CRF mechanisms in the hypothalamic–pituitary–adrenal axis have some contribution to the neurobiology of alcohol abuse and dependence, a pivotal role for extra-hypothalamic CRF pathways, particularly in the extended amygdala, is well characterized. More recent studies further suggest a direct modulation of brain reward function by CRF signaling in the ventral tegmental area, nucleus accumbens, and the prefrontal cortex, among other structures. This review will further discuss a putative role for other components of the CRF system that contribute for the overall balance of CRF function in reward and stress pathways, including CRF2 receptors, CRF-binding protein, and urocortins, a family of CRF-related peptides. PMID:27818644

Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone

PubMed Central

Besheer, Joyce; Fisher, Kristen R.; Lindsay, Tessa G.; Cannady, Reginald

2013-01-01

Stressful life events and chronic stressors have been associated with escalations in alcohol drinking. Stress exposure leads to the secretion of glucocorticoids (cortisol in the human; corticosterone (CORT) in the rodent). To model a period of heightened elevations in CORT, the present work assessed the effects of chronic exposure to the stress hormone CORT on alcohol self-administration. Male Long Evans rats were trained to self-administer a sweetened alcohol solution (2% sucrose/15% alcohol) resulting in moderate levels of daily alcohol intake (0.5–0.7 g/kg). Following stable baseline operant self-administration, rats received CORT in the drinking water for 7 days. A transient increase in alcohol self-administration was observed on the first self-administration session following CORT exposure, and behavior returned to control levels by the second session. Control experiments determined that this increase in alcohol self-administration was specific to alcohol, unrelated to general motor activation, and functionally dissociated from decreased CORT levels at the time of testing. These results indicate that repeated exposure to heightened levels of stress hormone (e.g., as may be experienced during stressful episodes) has the potential to lead to exacerbated alcohol intake in low to moderate drinkers. Given that maladaptive drinking patterns, such as escalated alcohol drinking following stressful episodes, have the potential to put an individual at risk for future drinking disorders, utilization of this model will be important for examination of neuroadaptations that occur as a consequence of CORT exposure in order to better understand escalated drinking following stressful episodes in nondependent individuals. PMID:23643750

The attributes of successful de-escalation and restraint teams.

PubMed

Snorrason, Jón; Biering, Páll

2018-06-04

Inpatient violence is a widespread problem on psychiatric wards often with serious consequences, and psychiatric hospitals have set up teams to de-escalate and restrain patients with aggression (D-E&R teams) which are specially trained to respond to it in a safe manner. Successful de-escalation and restraining of patients with aggression depend not only on the methods learned in training but also on the confidence of the team. Therefore, it is of great importance to understand the factors that enhance D-E&R teams' competence in managing patients with aggression in a successful and safe manner. The aim of this hermeneutic study was to identify and understand those factors. Purposive-expert sampling was used and twelve D-E&R team members with significant experience participated in the study. The central theme found was a safe team. Ensuring the safety of the team and its members was found to be a prerequisite for successful teamwork in managing patients with aggression in a safe manner. This central theme falls into two interacting domains: the internal dynamics of the team and the team's interaction with patients. Several themes, such as mutual trust, flexibility, and knowing one's role, influence these domains and hence strengthen or weaken the confidence and safety of the team. The findings of the study will contribute to a better understanding of these factors; understanding which could be used to improve the training, supervision, and quality assessment of D-E&R teams and hence lead to more safety in psychiatric wards. © 2018 Australian College of Mental Health Nurses Inc.

Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization

PubMed Central

Doherty, James M.; Frantz, Kyle J.

2012-01-01

Objectives Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization. Methods Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 hr, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 hr after the last injection, then every 24 hr for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at 4 points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation. Results A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages. Conclusion Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence. PMID:22941050

Impact of Sequential Culture Results on Diagnosis and De-Escalation of the Antibiotic Regimen in Joint and Bone Infections.

PubMed

Kernéis, Solen; Leprince, Cécile; Archambeau, Denis; Eyrolle, Luc; Leclerc, Philippe; Poupet, Hélène; Loubinoux, Julien; Gauzit, Rémy; Salmon, Dominique; Launay, Odile; Poyart, Claire; Anract, Philippe; Morand, Philippe C

According to existing guidelines, orthopedic specimens collected in joint and bone infections (JBI) in our institution are cultured on several media sets and incubated for two, seven, and 14 days. The optimal timing for de-escalation of the first-line antibiotic combination according to the culture results needs to be defined. Single-center, retrospective analysis of all adult patients with a first documented episode of JBI between May 2012 and April 2013. Ninety patients were included, 51 males (57%), median age 58 y (range 18-87 y), with prosthesis infection in 62 cases (69%). Rapidly growing pathogens (Staphylococcus aureus [n = 36] and Enterobacteriaceae [n = 12]) usually were diagnosed within two days, whereas coagulase-negative staphylococci (n = 25) and Propionibacterium acnes (n = 13) generally were identified after seven days (p < 10 -5 ). Positive culture results at day 2 fit with definitive microbiological diagnosis in 95% of cases, and prolonged incubation led to the identification of additional micro-organisms in only four of 76 patients (5%) with day-2-positive cultures. Conversely, for those with negative two-day culture (n = 14), the seven-day culture allowed identification of less virulent pathogens in eight cases (57%). Our results suggest that, in JBI, de-escalation of the empirical antibiotic regimen can be based on micro-organisms identified on the two-day culture set. The impact of such a strategy on clinical outcomes, antibiotic consumption, and costs needs to be assessed in larger studies.

Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.

PubMed

Furman, Wayne L; Crews, Kristine R; Billups, Catherine; Wu, Jianrong; Gajjar, Amar J; Daw, Najat C; Patrick, Christian C; Rodriguez-Galindo, Carlos; Stewart, Clinton F; Dome, Jeffrey S; Panetta, John C; Houghton, Peter J; Santana, Victor M

2006-02-01

Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu; Das, Shiva; Gu, Lin

2015-12-01

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standardmore » 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.« less

Demographic and socioenvironmental predictors of premorbid marijuana use among patients with first-episode psychosis.

PubMed

Pauselli, Luca; Birnbaum, Michael L; Vázquez Jaime, Beatriz Paulina; Paolini, Enrico; Kelley, Mary E; Broussard, Beth; Compton, Michael T

2018-01-31

We identified, in subjects with first-episode psychosis, demographic and socioenvironmental predictors of three variables pertaining to premorbid marijuana use: age at initiation of marijuana use, trajectories of marijuana use in the five years prior to onset of psychosis, and the cumulative "dose" of marijuana intake in that same premorbid period. We enrolled 247 first-episode psychosis patients and collected data on lifetime marijuana/alcohol/tobacco use, age at onset of psychosis, diverse socioenvironmental variables, premorbid adjustment, past traumatic experiences, perceived neighborhood-level social disorder, and cannabis use experiences. Bivariate tests were used to examine associations between the three premorbid marijuana use variables and hypothesized predictors. Regression models determined which variables remained independently significantly associated. Age at initiation of cigarette smoking was linked to earlier initiation, faster escalation, and higher cumulative dose of premorbid marijuana use. During childhood, poorer academic performance was predictive of an earlier age at initiation of marijuana use, while poorer sociability was related to more rapid escalation to daily use and a higher cumulative dose. As expected, experiencing euphoric effects was positively correlated with trajectories and cumulative dose, but having negative experiences was unrelated. Traumatic childhood/adolescent experiences were correlated with rapid escalation and amount of marijuana used, but not with age at initiation of marijuana use. These data expand the very limited literature on predictors of premorbid marijuana use in first-episode psychosis. Given its association with earlier age at onset of psychosis, and poorer outcomes among first-episode patients, prevention and treatment efforts should be further developed. Copyright © 2018 Elsevier B.V. All rights reserved.

Trajectories of substance use among young American Indian adolescents: patterns and predictors.

PubMed

Whitesell, Nancy Rumbaugh; Asdigian, Nancy L; Kaufman, Carol E; Big Crow, Cecelia; Shangreau, Carly; Keane, Ellen M; Mousseau, Alicia C; Mitchell, Christina M

2014-03-01

Substance use often begins earlier among American Indians compared to the rest of the United States, a troubling reality that puts Native youth at risk for escalating and problematic use. We need to understand more fully patterns of emergent substance use among young American Indian adolescents, risk factors associated with escalating use trajectories, and protective factors that can be parlayed into robust prevention strategies. We used growth mixture modeling with longitudinal data from middle-school students on a Northern Plains reservation (Wave 1 N = 381, M age at baseline = 12.77, 45.6% female) to identify subgroups exhibiting different trajectories of cigarette, alcohol, and marijuana use. We explored how both risk (e.g., exposure to stressful events, deviant peers) and protective (e.g., positive parent-child relationships, cultural identity) factors were related to these trajectories. For all substances, most youth showed trajectories characterized by low rates of substance use (nonuser classes), but many also showed patterns characterized by high and/or escalating use. Across substances, exposure to stress, early puberty, and deviant peer relationships were associated with the more problematic patterns, while strong relationships with parents and prosocial peers were associated with nonuser classes. Our measures of emergent cultural identity were generally unrelated to substance use trajectory classes among these young adolescents. The findings point to the importance of early substance use prevention programs for American Indian youth that attenuate the impact of exposure to stressful events, redirect peer relationships, and foster positive parent influences. They also point to the need to explore more fully how cultural influences can be captured.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Influences of Mood Variability, Negative Moods, and Depression on Adolescent Cigarette Smoking

PubMed Central

Weinstein, Sally M.; Mermelstein, Robin J.

2013-01-01

Understanding the emotional risk factors for cigarette smoking in adolescence can greatly inform prevention efforts. The current study examined prospective relationships between three affective dimensions – negative mood variability, overall negative mood, and depression, affect-related smoking motives, and future smoking patterns among adolescents. The current study expands on prior research by using real-time methods to assess mood and by focusing on a key developmental transition in smoking behavior: the progression from experimentation or low level, infrequent use to higher use. Ninth and 10th grade students (N = 461; 55% girls) provided data on cigarette use at a baseline and follow-up 15-month wave, and also provided ecological momentary assessments of negative moods via palmtop computers for one week at each wave. Negative mood was examined via the means of negative mood reports at each wave, and mood variability was examined via the intraindividual standard deviations of negative mood reports at each wave. Depressive symptoms and smoking motives were also assessed. Findings supported a complex self-medication model of smoking escalation in adolescence whereby mood-smoking relationships differed by affect dimension and gender. For girls, greater negative mood variability at baseline significantly predicted rapid escalation in smoking over time, whereas depressive symptoms and overall negative mood were unrelated to girls’ smoking patterns. In contrast, overall negative mood significantly predicted boys’ smoking escalation among those with affect-related motives for smoking. Results thus suggest that inconsistent mood-smoking relations in past work may be driven by the complex interrelationships among affect vulnerabilities, gender, and smoking patterns. PMID:23438244

Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies.

PubMed

Boyle, John; Craciunescu, Oana; Steffey, Beverly; Cai, Jing; Chino, Junzo

2014-11-01

To evaluate the safety of dose escalated radiotherapy using a simultaneous integrated boost technique in patients with locally advanced gynecological malignancies. Thirty-nine women with locally advanced gynecological malignancies were treated with intensity modulated radiation therapy utilizing a simultaneous integrated boost (SIB) technique for gross disease in the para-aortic and/or pelvic nodal basins, sidewall extension, or residual primary disease. Women were treated to 45Gy in 1.8Gy fractions to elective nodal regions. Gross disease was simultaneously treated to 55Gy in 2.2Gy fractions (n=44 sites). An additional sequential boost of 10Gy in 2Gy fractions was delivered if deemed appropriate (n=29 sites). Acute and late toxicity, local control in the treated volumes (LC), overall survival (OS), and distant metastases (DM) were assessed. All were treated with a SIB to a dose of 55Gy. Twenty-four patients were subsequently treated with a sequential boost to a median dose of 65Gy. Median follow-up was 18months. Rates of acute>grade 2 gastrointestinal (GI), genitourinary (GU), and hematologic (heme) toxicities were 2.5%, 0%, and 30%, respectively. There were no grade 4 acute toxicities. At one year, grade 1-2 late GI toxicities were 24.5%. There were no grade 3 or 4 late GI toxicities. Rates of grade 1-2 late GU toxicities were 12.7%. There were no grade 3 or 4 late GU toxicities. Dose escalated radiotherapy using a SIB results in acceptable rates of acute toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Problematic internet pornography use: The role of craving, desire thinking, and metacognition.

PubMed

Allen, Andrew; Kannis-Dymand, Lee; Katsikitis, Mary

2017-07-01

Defined as sexually explicit material that elicits erotic thoughts, feelings, and behaviours, internet pornography is a prevalent form of media that may facilitate problematic use and craving for engagement. Research suggests that superordinate cognitions and information processing, such as desire thinking and metacognition, are central to the activation and escalation of craving in addictive behaviours. The current study aimed to contribute to the literature by testing the proposed metacognitive model of desire thinking and craving in a sample of problematic pornography users, while revising the model by incorporating negative affect. From a theoretical perspective, environmental cues trigger positive metacognitions about desire thinking that directly influence desire thinking, resulting in the escalation of craving, negative metacognitions, and negative affect. Participants were recruited via an online survey and screened for problematic internet pornography use. Path analyses were used to investigate relationships among the aforementioned constructs in a final sample of 191 participants. Consistent with previous research, results of this study validated the existence of metacognitive processes in the activation of desire thinking and escalation of craving, while indicating that desire thinking has the potential to influence negative affect. Additionally, results supported the role of significant indirect relationships between constructs within the revised model of metacognition, desire thinking, and psychopathology. Collectively, the findings demonstrate the clinical value of a metacognitive conceptualisation of problematic pornography use. Exploring the metacognitive mechanisms that underpin problematic internet pornography use may give rise to the development of new treatment and relapse prevention strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Two New R&D 100 Awards Uphold NREL Winning Streak - Continuum Magazine |

Science.gov Websites

-effective and meet the demand for power. Solution: NREL, in partnership with Solar Junction, a manufacturer escalating power costs, brownouts, and rolling blackouts. Solution: NREL and its partners, AILR Research, Inc

ENVIRONMENTAL STEWARDSHIP OF PHARMACEUTICALS - THE GREEN PHARMACY

EPA Science Inventory

The occurrence of pharmaceuticals and personal care products (PPCPS) as environmental pollutants is a multifaceted issue whose scope continues to become better delineated since the escalation of conceited attention beginning in the 1980s. PPCPs typically occur as trace environme...

Louisiana mid-cycle survey shows change in forests resource trends

Treesearch

Charles E. Thomas; Carl V. Bylin

1982-01-01

Because costs of doing surveys are escalating rapidly, and both dollars and manpower are scarce resources, a low-intensity survey for the mid-cycle inventory may be the answer to timely monitoring of state resource trends.

Development of rational pay factors based on concrete compressive strength data

DOT National Transportation Integrated Search

2008-06-01

This research project addresses the opportunity to contain the escalating costs of concrete materials in construction projects. Both statistical process control and rational acceptance criteria show that quality improvement and cost savings can be ac...

To Address Suffering That the Majority Can't See: Lessons from Black Women's Leadership in the Workplace

ERIC Educational Resources Information Center

Dillard, Cynthia B.

2016-01-01

This chapter explores how both historically and in contemporary times of escalating violence against our bodies, minds, and spirits worldwide, Black women lead, love, and live within contexts of suffering.

Impact of obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for localized prostate cancer.

PubMed

Wang, Lora S; Murphy, Colin T; Ruth, Karen; Zaorsky, Nicholas G; Smaldone, Marc C; Sobczak, Mark L; Kutikov, Alexander; Viterbo, Rosalia; Horwitz, Eric M

2015-09-01

Previous publications have demonstrated conflicting results regarding body mass index (BMI) and prostate cancer (CaP) outcomes after definitive radiotherapy (RT) before the dose escalation era. The goal of the current study was to determine whether increasing BMI was associated with outcomes in men with localized CaP who were treated with dose-escalated RT. The authors identified patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity-modulated RT and image-guided RT from 2001 through 2010. BMI was analyzed as a continuous variable. Adjusting for confounders, multivariable competing risk and Cox proportional hazards regression models were used to assess the association between BMI and the risk of biochemical failure (BF), distant metastases (DM), cause-specific mortality (CSM), and overall mortality. Of the 1442 patients identified, approximately 20% had a BMI <25 kg/m(2) , 48% had a BMI of 25 to 29.9 kg/m(2) , 23% had a BMI of 30 to 34.9 kg/m(2) , 6% had a BMI of 35 to 39.9 kg/m(2) , and 4% had a BMI of ≥40 kg/m(2) . The median follow-up was 47.6 months (range, 1-145 months), with a median age of 68 years (range, 36-89 years). The median dose was 78 grays (range, 76-80 grays) and 30% of patients received androgen deprivation therapy. Increasing BMI was found to be inversely associated with age (P<.001) and pretreatment prostate-specific antigen level (P = .018). On multivariable analysis, increasing BMI was associated with an increased risk of BF (hazard ratio [HR], 1.03; 95% confidence interval [95% CI], 1.00-1.07 [P = .042]), DM (HR, 1.07; 95% CI, 1.02-1.11 [P = .004]), CSM (HR, 1.15; 95% CI, 1.07-1.23 [P<.001]), and overall mortality (HR, 1.05; 95% CI, 1.02-1.08 [P = .004]). For patients with CaP receiving dose-escalated intensity-modulated RT with daily image-guidance, increasing BMI appears to be associated with an increased risk of BF, DM, CSM, and overall mortality. © 2015 American Cancer Society.

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morris, W. James, E-mail: jmorris@bccancer.bc.ca; BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398more » trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.« less

ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodda, Sree; Tyldesley, Scott; Department of Surgery, University of British Columbia, Vancouver, British Columbia

Purpose: To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials: ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GUmore » and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results: The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT (P<.001). Compared with the cumulative incidence, the 5-year prevalence of grade 3 GU morbidity was substantially lower for both arms (8.6% vs 2.2%, P=.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT (P=.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT (P=.30). Conclusions: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of erectile dysfunction were observed.« less

Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miah, Aisha B.; Bhide, Shreerang A.; Guerrero-Urbano, M. Teresa

2012-02-01

Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and latemore » toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study.« less

Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice.

PubMed

Newman, Emily L; Gunner, Georgia; Huynh, Polly; Gachette, Darrel; Moss, Stephen J; Smart, Trevor G; Rudolph, Uwe; DeBold, Joseph F; Miczek, Klaus A

2016-11-01

Alcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABA A receptor α2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α2-containing GABA A receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking. Male wild-type (Wt) C57BL/6J and point-mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α2-containing GABA A receptors were assessed for their binge-like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH-naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.). Mice with BZD-insensitive α2-containing GABA A receptors (H101R) escalated their binge-like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild-types, they did not show forced abstinence-induced social deficits. These findings suggest a role for: (i) H101 in species-typical binge-like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence-associated social deficits. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive α2-containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABA A receptors by ALLO and THDOC; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic EtOH intake. Copyright © 2016 by the Research Society on Alcoholism.

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.

PubMed

Bendell, J; O'Reilly, E M; Middleton, M R; Chau, I; Hochster, H; Fielding, A; Burke, W; Burris, H

2015-04-01

Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. NCT00515866. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study.

PubMed

Ahn, Myung-Ju; Kim, Dong-Wan; Cho, Byoung Chul; Kim, Sang-We; Lee, Jong Seok; Ahn, Jin-Seok; Kim, Tae Min; Lin, Chia-Chi; Kim, Hye Ryun; John, Thomas; Kao, Steven; Goldman, Jonathan W; Su, Wu-Chou; Natale, Ronald; Rabbie, Sarit; Harrop, Bryony; Overend, Philip; Yang, Zhenfan; Yang, James Chih-Hsin

2017-11-01

CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases. This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced-stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369. Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day). AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies. AstraZeneca. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis of optimal usage of available aggregates in highway construction and maintenance.

DOT National Transportation Integrated Search

2009-11-01

The optimization of available aggregates for highway construction and maintenance is vital both from an economic and environmental perspective. By not optimizing the aggregate supply, project costs escalate as a simple response to supply and demand. ...

User accpetance of ATIS products and services : a report of qualitative research

DOT National Transportation Integrated Search

1992-08-01

In recent years, transportation planning has been experiencing an escalating emphasis towards increasing capacity and improving traffic management on urban streets and arterials to combat the effects of congestion. One measure which has proven to be ...

PERSONAL-PRACTICES POLLUTANTS: UBIETY, UBIQUITY, SIGNIFICANCE, SOLUTIONS, STEWARDSHIP

EPA Science Inventory

The occurrence of pharmaceuticals and personal care products (PPCPS) as environmental pollutants is a multifaceted issue whose scope continues to become better delineated with the escalation of attention that began in the 1980s. PPCPs typically occur as trace environmental pollut...

Fueling the future with fungal genomics

USDA-ARS?s Scientific Manuscript database

Rapidly growing human populations are escalating the demand for energy in our interdependent world. Limited fossil resources and negative ecological impacts of petroleum exploitation dictate the need to explore alternative energy sources. Cellulosic biofuels, the use of plant biomass to produce alco...

Reconstructing Human Exposures Using Biomarkers and other "Clues"

EPA Science Inventory

Biomonitoring is the process by which biomarkers are measured in human tissues and specimens to evaluate exposures. Given the growing number of population-based biomonitoring surveys, there is now an escalated interest in using biomarker data to reconstruct exposures for supporti...

2012 U.S. Marine Corps S&T Strategic Plan

DTIC Science & Technology

2012-01-17

29 Training and Education...required capabilities through Doctrine, Organization, Training , Materiel, Leadership and Education, Personnel, and Facilities (DOTMLPF) analysis to...Escalation of Force, Expeditionary Energy, Training and Education, and Irregular Warfare. e. The maneuver functional area specifically addresses the

Academic Capitalism and the Community College

ERIC Educational Resources Information Center

Kleinman, Ilene

2010-01-01

Profit-generating entrepreneurial initiatives have become increasingly important as community colleges look for alternative revenue to support escalating costs in an environment characterized by funding constraints. Academic capitalism was used as the conceptual framework to determine whether community colleges have become increasingly market…

76 FR 70807 - Notice of Passenger Facility Charge (PFC) Approvals and Disapprovals

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-15

... (design and construction). Enplane road structural improvements (design and construction). Landside signage improvements (design and construction). Taxiway B-2 extension and taxiway B-1 rehabilitation (design and construction). Elevator and escalator safety code compliance improvements (design and...

Financial Resources.

ERIC Educational Resources Information Center

Dougherty, Richard M.; And Others

1989-01-01

Nine articles cover topics related to library financial resources: (1) escalating serials prices; (2) library budgeting; (3) entrepreneurship; (4) cutback management; (5) academic library budgets; (6) assessment of library effectiveness; (7) public library fund-raising; (8) capital investment; and (9) unit cost analysis at the Virginia Polytechnic…

Now is the time to demand change to punishing FtP procedures.

PubMed

Mason, Sharon

2016-05-25

Having undergone Nursing and Midwifery Council fitness to practise (FtP) proceedings after raising and escalating concerns, I read with interest your article about nurses facing FtP hearings being 'pushed to breaking point' (analysis, May 11).

Followership Behaviors among Florida Community College Faculty

ERIC Educational Resources Information Center

Smith, John Scott

2009-01-01

As postsecondary institutions are confronted by the challenges of escalating accountability, shrinking budgets, and administrative downsizing, higher education leaders are expecting more from their faculty members. In this environment, an improved understanding of faculty followership behaviors is increasingly important. We examined the…

Risk-based asset management methodology for highway infrastructure systems.

DOT National Transportation Integrated Search

2004-01-01

Maintaining the infrastructure of roads, highways, and bridges is paramount to ensuring that these assets will remain safe and reliable in the future. If maintenance costs remain the same or continue to escalate, and additional funding is not made av...

Air-to-air heat recovery devices for small buildings : interim report

DOT National Transportation Integrated Search

1981-01-01

With the escalation of fuel costs, many people are turning to tighter, better insulated buildings as a means of achieving energy conservation. This is especially true in northern climates, where heating seasons are long and severe. Installing efficie...

Are proteomic technologies ready for IVDs

USDA-ARS?s Scientific Manuscript database

During the last decade as a result of the unparalleled advancements in mass spectrometry-based methods in protein analysis, biomarker research has escalated to new heights in the academic, government and industrial research laboratories. Translation of biomarker research to in vitro diagnostics (IVD...

Deep reinforcement learning for automated radiation adaptation in lung cancer.

PubMed

Tseng, Huan-Hsin; Luo, Yi; Cui, Sunan; Chien, Jen-Tzung; Ten Haken, Randall K; Naqa, Issam El

2017-12-01

To investigate deep reinforcement learning (DRL) based on historical treatment plans for developing automated radiation adaptation protocols for nonsmall cell lung cancer (NSCLC) patients that aim to maximize tumor local control at reduced rates of radiation pneumonitis grade 2 (RP2). In a retrospective population of 114 NSCLC patients who received radiotherapy, a three-component neural networks framework was developed for deep reinforcement learning (DRL) of dose fractionation adaptation. Large-scale patient characteristics included clinical, genetic, and imaging radiomics features in addition to tumor and lung dosimetric variables. First, a generative adversarial network (GAN) was employed to learn patient population characteristics necessary for DRL training from a relatively limited sample size. Second, a radiotherapy artificial environment (RAE) was reconstructed by a deep neural network (DNN) utilizing both original and synthetic data (by GAN) to estimate the transition probabilities for adaptation of personalized radiotherapy patients' treatment courses. Third, a deep Q-network (DQN) was applied to the RAE for choosing the optimal dose in a response-adapted treatment setting. This multicomponent reinforcement learning approach was benchmarked against real clinical decisions that were applied in an adaptive dose escalation clinical protocol. In which, 34 patients were treated based on avid PET signal in the tumor and constrained by a 17.2% normal tissue complication probability (NTCP) limit for RP2. The uncomplicated cure probability (P+) was used as a baseline reward function in the DRL. Taking our adaptive dose escalation protocol as a blueprint for the proposed DRL (GAN + RAE + DQN) architecture, we obtained an automated dose adaptation estimate for use at ∼2/3 of the way into the radiotherapy treatment course. By letting the DQN component freely control the estimated adaptive dose per fraction (ranging from 1-5 Gy), the DRL automatically favored dose escalation/de-escalation between 1.5 and 3.8 Gy, a range similar to that used in the clinical protocol. The same DQN yielded two patterns of dose escalation for the 34 test patients, but with different reward variants. First, using the baseline P+ reward function, individual adaptive fraction doses of the DQN had similar tendencies to the clinical data with an RMSE = 0.76 Gy; but adaptations suggested by the DQN were generally lower in magnitude (less aggressive). Second, by adjusting the P+ reward function with higher emphasis on mitigating local failure, better matching of doses between the DQN and the clinical protocol was achieved with an RMSE = 0.5 Gy. Moreover, the decisions selected by the DQN seemed to have better concordance with patients eventual outcomes. In comparison, the traditional temporal difference (TD) algorithm for reinforcement learning yielded an RMSE = 3.3 Gy due to numerical instabilities and lack of sufficient learning. We demonstrated that automated dose adaptation by DRL is a feasible and a promising approach for achieving similar results to those chosen by clinicians. The process may require customization of the reward function if individual cases were to be considered. However, development of this framework into a fully credible autonomous system for clinical decision support would require further validation on larger multi-institutional datasets. © 2017 American Association of Physicists in Medicine.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

PubMed

Cassier, Philippe A; Italiano, Antoine; Gomez-Roca, Carlos A; Le Tourneau, Christophe; Toulmonde, Maud; Cannarile, Michael A; Ries, Carola; Brillouet, Anne; Müller, Claudia; Jegg, Anna-Maria; Bröske, Ann-Marie; Dembowski, Markus; Bray-French, Katharine; Freilinger, Christine; Meneses-Lorente, Georgina; Baehner, Monika; Harding, Ross; Ratnayake, Jayantha; Abiraj, Keelara; Gass, Nathalie; Noh, Karen; Christen, Randolph D; Ukarma, Lidia; Bompas, Emmanuelle; Delord, Jean-Pierre; Blay, Jean-Yves; Rüttinger, Dominik

2015-08-01

Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. F Hoffmann-La Roche. Copyright © 2015 Elsevier Ltd. All rights reserved.

Using MAPP to Connect Communities: One County's Story

ERIC Educational Resources Information Center

Boyd, Rita Arras; Peters, Mark

2009-01-01

Public health leaders of the 21st century are challenged by increasingly complex problems and escalating expectations amid scarce or shrinking resources. Community and interdisciplinary collaboration holds promise for synergism and capacity building. Mobilizing for Action through Planning and Partnerships (MAPP), the latest…

78 FR 40619 - Combating Wildlife Trafficking

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-05

... follows: Section 1. Policy. The poaching of protected species and the illegal trade in wildlife and their... that continues to escalate. Poaching operations have expanded beyond small-scale, opportunistic actions... protected wildlife species such as elephants, rhinos, great apes, tigers, sharks, tuna, and turtles has...

Characterization of HMA mixtures containing high reclaimed asphalt pavement content with crumb rubber additives.

DOT National Transportation Integrated Search

2013-03-01

As the price of petroleum and material costs escalate and pressures of maintaining the sustainability of our environment, owners must continually find methods to decrease material costs and maximize their benefits. This paper presents the findings of...

UBIQUITOUS POLLUTANTS FROM CUMULATIVE PERSONAL PRACTICES - STEWARDSHIP OF THE WATER CYCLE

EPA Science Inventory

The occurrence of pharmaceuticals and personal care products (PPCPS) as environmental pollutants is a multifaceted issue whose scope continues to become better delineated since the escalation of concerted attention beginning in the 1980s. PPCPs typically occur as trace environmen...

Aviation Safety: FAA Has Begun Efforts to Make Data More Publicly Available

DOT National Transportation Integrated Search

1997-04-25

Public concern about the safety of the nation's aviation system escalated : following the crashes of ValuJet flight 592 and TWA flight 800. The Congress : and the public expressed interest in having the Federal Aviation Administration : (FAA) publish...

Program Performance Inventory: Six Juvenile Offender Programs.

ERIC Educational Resources Information Center

Thomalla, Terri Groff; Dougherty, Victoria J.

This report describes the performance of 6 Connecticut juvenile justice alternative sanction programs in 14 qualitative areas: community reintegration; outcomes and evaluation; assessment methods; risk factors; escalation of criminal activity; family involvement; community involvement; work ethic and vocational training; education and life skills;…

Investing in Rare Books and Manuscripts

PubMed Central

Liebert, Herman W.

1981-01-01

The lecture treats the rapidly escalating values of rare books and manuscripts both as financial and as scholarly investments. The text suggests new areas for collecting which may be pursued in today's market with an eye to an increasing intellectual and monetary return. PMID:7324508

Developing cost effective plans for low volume bridges

DOT National Transportation Integrated Search

2006-09-01

There is currently an escalating concern across the state of Kansas with respect to the age : and condition of low volume bridges and methods available to modify or replace them. A : high percentage of low volume bridges in the state of Kansas requir...

75 FR 66739 - Technology Innovation Program (TIP) Seeks White Papers

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-29

... network analyses in the following areas--sustainable manufacturing models, resource management and... manufacturing, all endeavors require energy as input. Escalating energy demands throughout the world can lead to... such as: Technologies for improved manufacturing of critical components for alternative energy...

26 CFR 1.856-3 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., the wiring in a building, plumbing systems, central heating, or central air-conditioning machinery, pipes or ducts, elevators or escalators installed in the building, or other items which are structural... operation of a business, such as machinery, printing press, transportation equipment which is not a...

26 CFR 1.856-3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

..., the wiring in a building, plumbing systems, central heating, or central air-conditioning machinery, pipes or ducts, elevators or escalators installed in the building, or other items which are structural... operation of a business, such as machinery, printing press, transportation equipment which is not a...

26 CFR 1.856-3 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., the wiring in a building, plumbing systems, central heating, or central air-conditioning machinery, pipes or ducts, elevators or escalators installed in the building, or other items which are structural... operation of a business, such as machinery, printing press, transportation equipment which is not a...

26 CFR 1.856-3 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., the wiring in a building, plumbing systems, central heating, or central air-conditioning machinery, pipes or ducts, elevators or escalators installed in the building, or other items which are structural... operation of a business, such as machinery, printing press, transportation equipment which is not a...

Microcomputers in the Anesthesia Library.

ERIC Educational Resources Information Center

Wright, A. J.

The combination of computer technology and library operation is helping to alleviate such library problems as escalating costs, increasing collection size, deteriorating materials, unwieldy arrangement schemes, poor subject control, and the acquisition and processing of large numbers of rarely used documents. Small special libraries such as…

Factors associated with opioid dose increases: a chart review of patients’ first year on long-term opioids

PubMed Central

Bautista, Christopher A.; Iosif, Ana-Maria; Wilsey, Barth L.; Melnikow, Joy A.; Crichlow, Althea; Henry, Stephen G.

2016-01-01

OBJECTIVE To examine encounter-level factors associated with opioid dose increases during patients’ first year on opioid therapy for chronic pain. DESIGN Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type; opioid dose change; documented prescribing rationale; documentation of guideline-concordant opioid prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. RESULTS 674 encounters were coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with email encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared to face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95%CI 0.11 – 0.28) and email (OR 0.23, 95%CI 0.12 – 0.47) encounters; documentation of prescribing rationale was significantly more likely for email (OR 5.06, 95%CI 1.87–13.72) and less likely for telephone (OR 0.30, 95%CI 0.18–0.51) encounters. CONCLUSION Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation. PMID:27477581

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org; Henderson, Randal; Pham, Dat

Purpose: Proton therapy has been shown to reduce radiation dose to organs at risk (OAR) and could be used to safely escalate the radiation dose. We analyzed outcomes in a group of phase 2 study patients treated with dose-escalated proton therapy with concurrent chemotherapy for stage 3 non-small cell lung cancer (NSCLC). Methods and Materials: From 2009 through 2013, LU02, a phase 2 trial of proton therapy delivering 74 to 80 Gy at 2 Gy/fraction with concurrent chemotherapy for stage 3 NSCLC, was opened to accrual at our institution. Due to slow accrual and competing trials, the study was closed after justmore » 14 patients (stage IIIA, 9 patients; stage IIIB, 5 patients) were accrued over 4 years. During that same time period, 55 additional stage III patients were treated with high-dose proton therapy, including 7 in multi-institutional proton clinical trials, 4 not enrolled due to physician preference, and 44 who were ineligible based on strict entry criteria. An unknown number of patients were ineligible for enrollment due to insurance coverage issues and thus were treated with photon radiation. Median follow-up of surviving patients was 52 months. Results: Two-year overall survival and progression-free survival rates were 57% and 25%, respectively. Median lengths of overall survival and progression-free survival were 33 months and 14 months, respectively. There were no acute grade 3 toxicities related to proton therapy. Late grade 3 gastrointestinal toxicity and pulmonary toxicity each occurred in 1 patient. Conclusions: Dose-escalated proton therapy with concurrent chemotherapy was well tolerated with encouraging results among a small cohort of patients. Unfortunately, single-institution proton studies may be difficult to accrue and consideration for pragmatic and/or multicenter trial design should be considered when developing future proton clinical trials.« less

A phase II, multicentre trial evaluating the efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal-related events.

PubMed

Addison, Christina L; Bouganim, Nathaniel; Hilton, John; Vandermeer, Lisa; Dent, Susan; Amir, Eitan; Hopkins, Sean; Kuchuk, Iryna; Segal, Roanne; Song, Xinni; Gertler, Stan; Mazzarello, Sasha; Dranitsaris, George; Ooi, Daylily; Pond, Gregory; Clemons, Mark

2014-04-01

The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3-4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600 ng/L after ≥3 months of 3-4 weekly IV pamidronate were switched to 12 weekly therapy for 48 weeks. Primary endpoint was the proportion of patients maintaining CTx levels in the lower-risk range. All endpoints (serum CTx and bone-specific alkaline phosphatase (BSAP), skeletal-related events (SREs) and self-reported pain) were measured at baseline, 6, 12, 24, 36 and 48 weeks. Treatment failure was defined as biochemical failure (CTx > 600 ng/L) or a SRE. Exploratory biomarkers including; serum TGF-β, activin-A, bone sialoprotein (BSP), procollagen type 1 N-terminal propeptide and urinary N-telopeptide (NTx) were assessed at baseline as predictors for failure to complete treatment. Seventy-one patients accrued and 43 (61 %) completed 48 weeks of de-escalated therapy. Reasons for failure to complete treatment included; biochemical failure (CTx > 600 ng/L) (n = 10, 14.1 %), on-study SRE (n = 9, 12.7 %), disease progression (n = 7, 9.9 % including death from disease [n = 1, 1.4 %]) or patient choice (n = 2, 2.8 %). Elevated baseline levels of CTx, BSAP, NTx and BSP were associated with treatment failure. The majority of patients in this biochemically defined low-risk population could switch from 3-4 weekly to 12 weekly bisphosphonate therapy with no effect on CTx levels or SREs during the 48 week study. Larger trials are required to assess the roles of biomarkers as predictors of adequacy of de-escalated therapy.

Community Based Flood Modeling in Southern and Baja California to Meet End User Needs for Decision-Making

NASA Astrophysics Data System (ADS)

Sanders, B. F.

2017-12-01

Flooding of coastal and fluvial systems are the most significant natural hazards facing society, and damages have been escalating for decades globally and in the U.S. Almost all metropolitan areas are exposed to flood risk. The threat from river flooding is especially high in India and China, and coastal cities around the world are threatened by storm surge and rising sea levels. Several trends including rising sea levels, urbanization, deforestation, and rural-to-urban population shifts will increase flood exposure in the future. Flood impacts are escalating despite advances in hazards science and extensive effort to manage risks. The fundamental issue is not that flooding is becoming more severe, even though it is in some places, but rather that societies are become more vulnerable to flood impacts. A critical factor contributing to the escalation of flood impacts is that the most vulnerable sectors of communities are left out of processes to prepare for and respond to flooding. Furthermore, the translation of knowledge about flood hazards and vulnerabilities into actionable information for communities has not been effective. In Southern and Baja California, an interdisciplinary team of researchers has partnered with stakeholders in flood vulnerable communities to co-develop flood hazard information systems designed to meet end-user needs for decision-making. The initiative leveraged the power of advanced, fine-scale hydraulic models of flooding to craft intuitive visualizations of context-sensitive scenarios. This presentation will cover the ways by which the process of flood inundation modeling served as a focal point for knowledge development, as well as the unique visualizations that populate on-line information systems accessible here: http://floodrise.uci.edu/online-flood-hazard-viewers/

Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

PubMed Central

Buggy, Joseph J.; Sharman, Jeff P.; Smith, Sonali M.; Boyd, Thomas E.; Grant, Barbara; Kolibaba, Kathryn S.; Furman, Richard R.; Rodriguez, Sara; Chang, Betty Y.; Sukbuntherng, Juthamas; Izumi, Raquel; Hamdy, Ahmed; Hedrick, Eric; Fowler, Nathan H.

2013-01-01

Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. PMID:23045577

Phase I Trial of Anti-CS1 Monoclonal Antibody Elotuzumab in Combination With Bortezomib in the Treatment of Relapsed/Refractory Multiple Myeloma

PubMed Central

Jakubowiak, Andrzej J.; Benson, Don M.; Bensinger, William; Siegel, David S.D.; Zimmerman, Todd M.; Mohrbacher, Ann; Richardson, Paul G.; Afar, Daniel E.H.; Singhal, Anil K.; Anderson, Kenneth C.

2012-01-01

Purpose To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM). Patients and Methods Elotuzumab (2.5, 5.0, 10, or 20 mg/kg intravenously [IV]) and bortezomib (1.3 mg/m2 IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria. Results Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months. Conclusion The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM. PMID:22291084

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin

2013-03-15

Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likelymore » to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.« less

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PubMed

Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

2016-01-01

The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. NCT01149343, Results.

American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer.

PubMed

Spratt, Daniel E; Soni, Payal D; McLaughlin, Patrick W; Merrick, Gregory S; Stock, Richard G; Blasko, John C; Zelefsky, Michael J

To review outcomes for high-risk prostate cancer treated with combined modality radiation therapy (CMRT) utilizing external beam radiation therapy (EBRT) with a brachytherapy boost. The available literature for high-risk prostate cancer treated with combined modality radiation therapy was reviewed and summarized. At this time, the literature suggests that the majority of high-risk cancers are curable with multimodal treatment. Several large retrospective studies and three prospective randomized trials comparing CMRT to dose-escalated EBRT have demonstrated superior biochemical control with CMRT. Longer followup of the randomized trials will be required to determine if this will translate to a benefit in metastasis-free survival, disease-specific survival, and overall survival. Although greater toxicity has been associated with CMRT compared to EBRT, recent studies suggest that technological advances that allow better definition and sparing of critical adjacent structures as well as increasing experience with brachytherapy have improved implant quality and the toxicity profile of brachytherapy. The role of androgen deprivation therapy is well established in the external beam literature for high-risk disease, but there is controversy regarding the applicability of these data in the setting of dose escalation. At this time, there is not sufficient evidence for the omission of androgen deprivation therapy with dose escalation in this population. Comparisons with surgery remain limited by differences in patient selection, but the evidence would suggest better disease control with CMRT compared to surgery alone. Due to a series of technological advances, modern combination series have demonstrated unparalleled rates of disease control in the high-risk population. Given the evidence from recent randomized trials, combination therapy may become the standard of care for high-risk cancers. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu; Ayala, Deandra; Jensen, Courtney

2012-02-01

Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patientsmore » experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.« less

Anti-TNF therapy for paediatric IBD: the Scottish national experience.

PubMed

Cameron, F L; Wilson, M L; Basheer, N; Jamison, A; McGrogan, P; Bisset, W M; Gillett, P M; Russell, R K; Wilson, D C

2015-04-01

Biological agents are being increasingly used in the UK for paediatric-onset inflammatory bowel disease (PIBD) despite limited evidence and safety concerns. We evaluated effectiveness and safety in the clinical setting, highlighting drug cost pressures, using our national Scottish PIBD biological registry. Complete usage of the biological agents, infliximab (IFX) and adalimumab (ADA) for treatment of PIBD (in those aged <18 years) from 1 January 2000 to 30 September 2010 was collated from all treatments administered within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN) national managed service network (all regional PGHAN centres and paediatric units within their associated district general hospitals). 132 children had biological therapy; 24 required both agents; 114 had Crohn's disease (CD), 16 had ulcerative colitis (UC) and 2 had IBD Unclassified (IBDU). 127 children received IFX to induce remission; 61 entered remission, 49 had partial response and 17 had no response. 72 were given maintenance IFX and 23 required dose escalation. 18 had infusion reactions and 27 had adverse events (infections/other adverse events). 29 had ADA to induce remission (28 CD and 1 UC), 24 after IFX; 10 entered remission, 12 had partial response and 7 had no response. All had maintenance; 19 required dose escalation. 12 children overall required hospitalisation due to drug toxicity. No deaths occurred with either IFX or ADA. Complete accrual of the Scottish nationwide 'real-life' experience demonstrates moderate effectiveness of anti tumour necrosis factor agents in severe PIBD but duration of effect is limited; significant financial issues (drug cost-need for dose escalation and/or multiple biological usage) and safety issues exist. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

PubMed

Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

2013-09-01

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

Do all patients in the phase I oncology trials need to be hospitalized? Domestic but outstanding issues for globalization of drug development in Japan.

PubMed

Shimomura, Akihiko; Kondo, Shunsuke; Kobayashi, Noriko; Iwasa, Satoru; Kitano, Shigehisa; Tamura, Kenji; Fujiwara, Yutaka; Yamamoto, Noboru

2017-08-01

Most trials investigating new drugs around the world, including phase I trials, are conducted in outpatient clinics. However, in Japan, regulatory authority requirements and traditional domestic guidelines often require hospitalization of phase I study participants. Patients participating in single-agent phase I clinical trials at National Cancer Center Hospital between December 1996 and August 2014 were monitored. Toxicity requiring hospitalization is defined as toxicity that needs intensive treatment. Study designs were classified into three types: first-in-human (FIH) study, dose-escalation study (conventional dose-escalation study to determine maximum tolerated dose (MTD) in Japanese patients), and dose-finding study (to assess safety and pharmacokinetic profiles up to the MTD previously determined in the West). A total of 945 patients who participated in a variety of single-agent phase I clinical trials between December 1996 and August 2014 were included in this study. Patients participated in one of three study types: dose-escalation (n = 582, 62%), first-in-human (n = 129, 14%), or dose-finding (n = 234, 25%). A total of 76 study drugs were evaluated as part of this pool of phase I studies. Subdivided by mechanism of action, 20 (26%) were cytotoxic, 50 (66%) were molecularly targeted, and 6 (8%) were immune checkpoint inhibitor. Thirty-six patients (3.8%) had severe toxicities requiring hospitalization during the first cycle. The overall number of toxicities requiring hospitalization and/or grade 4 toxicities during any cycle was 5.0%. The frequency of severe toxicity that needs to be hospitalized was unexpectedly low. The data did not demonstrate the need for hospitalization in the phase I trials, suggesting that phase I trials in Japan could be conducted in outpatient settings.

Clinical Outcomes of Golimumab as First, Second or Third Anti-TNF Agent in Patients with Moderate-to-Severe Ulcerative Colitis.

PubMed

Taxonera, Carlos; Rodríguez, Cristina; Bertoletti, Federico; Menchén, Luís; Arribas, Julia; Sierra, Mónica; Arias, Lara; Martínez-Montiel, Pilar; Juan, Alba; Iglesias, Eva; Algaba, Alicia; Manceñido, Noemí; Rivero, Montserrat; Barreiro-de Acosta, Manuel; López-Serrano, Pilar; Argüelles-Arias, Federico; Gutierrez, Ana; Busquets, David; Gisbert, Javier P; Olivares, David; Calvo, Marta; Alba, Cristina

2017-08-01

Golimumab efficacy data in ulcerative colitis (UC) are limited to anti-tumor necrosis factor α (TNF)-naive patients. The aim of this study was to assess the short-term and long-term efficacy of golimumab used as first, second, or third anti-TNF in UC in a real-life clinical setting. This retrospective multicenter cohort study included patients with moderate-to-severe UC treated with golimumab. The primary efficacy endpoints were short-term partial Mayo score response, long-term golimumab failure-free survival, and colectomy-free survival. In 142 patients with UC, golimumab was administered as first (40%), second (23%), or third anti-TNF (37%). Ninety-two patients (65%, 95% confidence interval 56.6-73) achieved short-term clinical response. Forty-five patients (32%, 95% confidence interval 23.7-39.7) achieved clinical remission. Response rates for golimumab were 75% as first anti-TNF, 70% as second anti-TNF (ns versus first anti-TNF), and 50% as third anti-TNF (P = 0.007 versus first anti-TNF). After 12 months median follow-up (interquartile range 6-18), 60 patients (42%, 95% confidence interval 34-51) had golimumab failure, and 15 patients (11%) needed colectomy. Thirty-one patients (22%) needed golimumab dose escalation, and 71% of these regained response after escalation. Starting maintenance with 100 mg golimumab doses and short-term nonresponse were independent predictors of golimumab failure. In this real-life cohort of patients with UC, golimumab therapy was effective for inducing and maintaining clinical response. Although anti-TNF-naive patients had better outcomes, golimumab was also effective in anti-TNF-experienced patients. Only the patients given golimumab after previous failure of 2 anti-TNF agents had significantly worse outcomes. Golimumab dose escalation was beneficial and safe.

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase.

PubMed

Engelmann, Alexander J; Aparicio, Mark B; Kim, Airee; Sobieraj, Jeffery C; Yuan, Clara J; Grant, Yanabel; Mandyam, Chitra D

2014-03-01

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2'-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

PubMed Central

Engelmann, Alexander J.; Aparicio, Mark B.; Kim, Airee; Sobieraj, Jeffery C.; Yuan, Clara J.; Grant, Yanabel

2013-01-01

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2′-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake. PMID:23443965

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma1

PubMed Central

Quinn, Jennifer A.; Reardon, David A.; Friedman, Allan H.; Rich, Jeremy N.; Sampson, John H.; Vredenburgh, James; Gururangan, Sridharan; Provenzale, James M.; Walker, Amy; Schweitzer, Holly; Bigner, Darell D.; Tourt-Uhlig, Sandra; Herndon, James E.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah; Ziegler, Karen; Bohlin, Cindy; Lentz, Christy; Friedman, Henry S.

2004-01-01

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs. PMID:15134629

Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.

Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dosemore » at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.« less

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Randomized Double-Blinded Dose Escalation Trial of Triptorelin for Ovary Protection in Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Brunner, Hermine I.; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C.; Imundo, Lisa; Williams, Calvin B.; Wallace, Carol A; Aikawa, Nadia E.; Nelson, Shannen; Klein-Gitelman, Marisa S.; Rose, Susan R.

2015-01-01

Objectives To determine for females with childhood-onset systemic lupus erythematosus (cSLE) who require cyclophosphamide the dose of triptorelin that suffices to maintain complete ovarian suppression (COS); measure the time needed to achieve ovarian suppression after triptorelin initiation, and explore the safety of triptorelin. Methods In this randomized double-blind placebo-controlled dose-escalation study females (< 21 years) were randomized 4:1 to receive triptorelin or placebo (25 triptorelin, 6 placebo). Starting doses of triptorelin between 25 and 100 microgram/kg/dose were used. Triptorelin dosage was escalated until COS was maintained. The primary outcome was the weight-adjusted dose of triptorelin that for at least 90% of the patients provides COS based on Gonadotropin-releasing-hormone Agonist Stimulation Testing. Secondary outcomes were time to ovarian suppression measured by unstimulated FSH and LH levels after study drug initiation. Results Triptorelin dosed at 120 microgram/kg bodyweight led to sustained COS in 90% of the patients. After the initial dose of triptorelin 22 days were needed for achieve COS. Rates of adverse events (AE) and serious adverse events (SAE) per 100 patient-month of follow-up were not higher in the triptorelin group as compared to the placebo group (triptorelin vs. placebo; AE: 189 vs. 362; SAE: 2.05 vs. 8.48). Conclusions For achieving and maintaining COS high doses of triptorelin are needed but appear to be well tolerated in adolescent females with cSLE. Our data suggest that a lag time of 22 days after triptorelin initiation is required before starting or continuing cyclophosphamide-therapy. Trial Registration Number clinicaltrials.gov identifier: NCT00124514 PMID:25676588

Combined MTOR and autophagy inhibition

PubMed Central

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O’Dwyer, Peter J; Amaravadi, Ravi K

2014-01-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted. PMID:24991838

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

2014-08-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Dose Escalation of Whole-Brain Radiotherapy for Brain Metastases From Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Heisterkamp, Christine; Huttenlocher, Stefan

2010-06-01

Purpose: The majority of patients with brain metastases from melanoma receive whole-brain radiotherapy (WBRT). However, the results are poor. Hypofractionation regimens failed to improve the outcome of these patients. This study investigates a potential benefit from escalation of the WBRT dose beyond the 'standard' regimen 30 Gy in 10 fractions (10x3 Gy). Methods and Materials: Data from 51 melanoma patients receiving WBRT alone were retrospectively analyzed. A dosage of 10x3 Gy (n = 33) was compared with higher doses including 40 Gy/20 fractions (n = 11) and 45 Gy/15 fractions (n = 7) for survival (OS) and local (intracerebral) controlmore » (LC). Additional potential prognostic factors were evaluated: age, gender, performance status, number of metastases, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: At 6 months, OS rates were 27% after 10x3 Gy and 50% after higher doses (p = 0.009). The OS rates at 12 months were 4% and 20%. On multivariate analysis, higher WBRT doses (p = 0.010), fewer than four brain metastases (p = 0.012), no extracerebral metastases (p = 0.006), and RPA class 1 (p = 0.005) were associated with improved OS. The LC rates at 6 months were 23% after 10x3 Gy and 50% after higher doses (p = 0.021). The LC rates at 12 months were 0% and 13%. On multivariate analysis, higher WBRT doses (p = 0.020) and fewer than brain metastases (p = 0.002) were associated with better LC. Conclusions: Given the limitations of a retrospective study, the findings suggest that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy. The hypothesis generated by this study must be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Factors Associated With Police Decisions on Immediate Responses to Intimate Partner Violence.

PubMed

Nesset, Merete Berg; Bjørngaard, Johan Håkon; Nøttestad, Jim Aage; Whittington, Richard; Lynum, Cecilie; Psychol, Cand; Palmstierna, Tom

2017-05-01

Police officers are often the first responders to intimate partner violence. The aim of the study was to examine the association between structured police assessments on-site in cases of intimate partner violence, and decisions about immediate arrest of the perpetrator and/or relocation of the victim. Data were extracted from police reports on 124 emergency visits in cases of intimate partner violence perpetrated by men toward women. Six out of totally 15 items of the intimate partner violence risk assessment measure B-SAFER were used by the front line police officers as the basis for decisions on whether or not to arrest the perpetrator or relocate the victim. The six items: perpetrator violent acts, violent threats or thoughts, escalation of violence, substance use problems, mental health problems, and breach of no-contact order, were selected on the basis of their utility in emergency situations. There were increased odds of arrest on-site if the perpetrator was physically violent (adjusted odds ratio [AOR] = 2.8, 95% confidence interval [CI] = 1.0-7.7) or had substance problems (AOR = 2.3, 95% CI = [1.0- 5.2]). There were increased odds of victim relocation if the perpetrator had mental health problems (AOR = 7.4, 95% CI = [2.4-23.1]) or if children were present on-site (AOR = 3.1, 95% CI = [1.1- 8.6]). In contrast, escalation of violence was associated with reduced odds of the perpetrator being arrested (AOR = 0.4, 95% CI = [0.1- 0.9]) or the victim being relocated (AOR = 0.4, 95% CI = [0.1- 1.3]). The finding that the police did not immediately respond to escalation, potentially signaling lethal violence needs to be addressed.

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

Evaluation of Antimicrobial Stewardship-Related Alerts Using a Clinical Decision Support System.

PubMed

Ghamrawi, Riane J; Kantorovich, Alexander; Bauer, Seth R; Pallotta, Andrea M; Sekeres, Jennifer K; Gordon, Steven M; Neuner, Elizabeth A

2017-11-01

Background: Information technology, including clinical decision support systems (CDSS), have an increasingly important and growing role in identifying opportunities for antimicrobial stewardship-related interventions. Objective: The aim of this study was to describe and compare types and outcomes of CDSS-built antimicrobial stewardship alerts. Methods: Fifteen alerts were evaluated in the initial antimicrobial stewardship program (ASP) review. Preimplementation, alerts were reviewed retrospectively. Postimplementation, alerts were reviewed in real-time. Data collection included total number of actionable alerts, recommendation acceptance rates, and time spent on each alert. Time to de-escalation to narrower spectrum agents was collected. Results: In total, 749 alerts were evaluated. Overall, 306 (41%) alerts were actionable (173 preimplementation, 133 postimplementation). Rates of actionable alerts were similar for custom-built and prebuilt alert types (39% [53 of 135] vs 41% [253 of 614], P = .68]. In the postimplementation group, an intervention was attempted in 97% of actionable alerts and 70% of interventions were accepted. The median time spent per alert was 7 minutes (interquartile range [IQR], 5-13 minutes; 15 [12-17] minutes for actionable alerts vs 6 [5-7] minutes for nonactionable alerts, P < .001). In cases where the antimicrobial was eventually de-escalated, the median time to de-escalation was 28.8 hours (95% confidence interval [CI], 10.0-69.1 hours) preimplementation vs 4.7 hours (95% CI, 2.4-22.1 hours) postimplementation, P < .001. Conclusions: CDSS have played an important role in ASPs to help identify opportunities to optimize antimicrobial use through prebuilt and custom-built alerts. As ASP roles continue to expand, focusing time on customizing institution specific alerts will be of vital importance to help redistribute time needed to manage other ASP tasks and opportunities.