bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exact Logic and Fault Simulation in Presence of Unknowns
Authors: Erb Dominik , Kochte Michael A. , Sauer Matthias , Hillebrecht Stefan , Schubert Tobias , Wunderlich Hans-Joachim , Becker Bernd 
Published: June 2014

Logic and fault simulation are essential techniques in electronic design automation. The accuracy of standard simulation algorithms is compromised by unknown or X-values. This results in a pessimistic overestimation of X-valued signals in the circuit and a pessimistic underestimation of fault coverage.
This work proposes efficient algorithms for combinational and sequential logic as well as for stuck-at and transition-delay fault simulation that are free of any simulation pessimism in presence of unknowns. The SAT-based algorithms exactly classifiy all signal states. During fault simulation, each fault is accurately classified as either undetected, definitely detected, or possibly detected.
The pessimism with respect to unknowns present in classic algorithms is thoroughly investigated in the experimental results on benchmark circuits. The applicability of the proposed algorithms is demonstrated on larger industrial circuits. The results show that, by accurate analysis, the number of detected faults can be significantly increased without increasing the test-set size.
MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence
Authors: Tabor Vedrana , Bocci Matteo , Alikhani Nyosha , Kuiper Raoul , Larsson Lars-Gunnar 
Published: June 2014

Abstract
The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence, a major barrier imposed on tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether MYC has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen-regulatable MycER, we show that tamoxifen-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose-dependent manner, resulting in reduced survival. Furthermore, MYC activation leads to reduced expression of the senescence markers p16INK4A, p21CIP1, and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by tamoxifen withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1, and reduced number of Ki67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process, with implications for future treatment strategies. Cancer Res; 74(16); 4222–9. ©2014 AACR.
In Vivo Regulation of Human Glutathione Transferase GSTP by Chemopreventive Agents
Authors: Henderson Colin J. , McLaren Aileen W. , Wolf C. Roland 
Published: June 2014

Abstract
Relatively little progress has been made in determining the in vivo regulation of glutathione S-transferase P (GSTP), particularly the human enzyme hGSTP1, despite being identified as a significant factor in carcinogenesis and development of drug resistance in tumor cell lines. Here, we report the characterization of a transgenic reporter mouse that reveals how hGSTP1 is regulated in vivo by chemopreventive agents. Basal expression was found in crypts and villi of the small and large intestine, bronchiolar epithelial cells, the epidermis and hair follicles, gall bladder epithelium, choroid plexus, and biliary epithelium. Expression was induced in different tissues by the antioxidant chemopreventive agents ethoxyquin and butylated hydroxyanisole. However, genetic deletion of the Nrf2 transcription factor, which directs central genetic programs of detoxification and protection against oxidative stress, increased rather than attenuated GSTP1 expression. In vitro investigations with mouse embryonic fibroblasts revealed factors, in addition to Nrf2, that control the expression of GSTP1, offering further insights into regulation. The new reporter mouse described here provides a useful tool to gain deeper insights into the mechanisms of action of chemopreventive compounds and other environmental agents. Cancer Res; 74(16); 4378–87. ©2014 AACR.
Of Mice, Rats, and Men: Could Nrf2 Activation Protect against Aflatoxin Heptocarcinogenesis in Humans?
Authors: Eaton David L. , Schaupp Christopher M. 
Published: June 2014

Abstract
In this issue, Johnson and colleagues provide a remarkable demonstration of the potential for “chemoprevention” of cancer from mutagenic chemicals. The authors demonstrated complete protection of rats from a carcinogenic treatment regimen with the potent dietary mutagen and hepatocarcinogen, aflatoxin B1 (AFB) by pretreatment with a synthetic oleanane triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). This study is notable for two reasons: (i) Activation of the Nrf2/Keap1/ARE “antioxidant response” pathway by CDDO-Im conferred complete protection against AFB-induced hepatocellular carcinomas in the Fisher F344 rat (a strain frequently used in life-time carcinogenicity bioassays), and (ii) extensive AFB–DNA adduct formation was seen in all animals at early time points, including those treated with CDDO-Im, albeit at lower levels (∼30% of the untreated animals), suggesting a strong divergence in the association between early DNA-damaging events, and tumor formation later in life. The authors suggest that this provides compelling experimental support for the concept of carcinogenic “thresholds” for mutagenic chemicals, because the treatment reduced persistent, mutagenic adducts (AFB–FAPyr adducts) only by 70%, but nearly completely eliminated tumors after approximately 2 years and preneoplastic lesions 6 weeks after the last dose of AFB. Cancer Prev Res; 7(7); 653–7. ©2014 AACR.
Variações da pressão intracraniana durante manobra de expansão pulmonar em pacientes com trauma cranioencefálico grave, monitorizados em unidade de terapia intensiva
Authors: Ferreira Silvia Aparecida , Israel Vera L. , Aguiar Luiz R. 
Published: June 2014

A fisioterapia dispõe de recursos específicos para a reabilitação em unidade de terapia intensiva (UTI), assim como nos pacientes com traumatismo cranioencefálico (TCE) grave. Entre essas técnicas, destaca- se a manobra de expansão pulmonar, que é uma técnica cinesioterapêutica, a qual tem função de mobilizar secreção pulmonar, prevenir e tratar atelectasias. Modelo do estudo: O estudo foi classificado como pesquisa de campo (experimental), baseada em avaliação da PIC durante e após a manobra de expansão pulmonar. Objetivo: Verificar a influência da manobra fisioterapêutica de expansão pulmonar nos valores da pressão intracraniana (PIC) em pacientes com TCE grave. Metodologia: A pesquisa foiaprovada pelo Comitê de Ética e Pesquisa da PUCPR, com o parecer 1455. Foi realizada na unidade de terapia intensiva (UTI) do Hospital Universitário Cajuru, Curitiba-PR. Participaram do estudo 15 pacientes de ambos os sexos, com TCE grave e com faixa etária entre 18 e 50 anos. As variáveis monitorizadas foram a PIC, a pressão arterial média (PAM) e a pressão de perfusão cerebral (PPC). Resultados: Durante a aplicação do protocolo de pesquisa observou-se que a PAM e a PPC mantiveram-se dentro ou próximos da normalidade com mínimas variações, enquanto que a PIC evolui com variação aproximada de 1 mmHg retornando aos valores iniciais. As médias da PIC no 1º dia, 2º dia e 3º dia foram 5,42 (±4,69) mmHg, 6,71 (±6,84) mmHg e 5,60 (±4,33) mmHg, com significância estatística respectivamente p<0,001, p=0,008 e p=0,001. Conclusões: A manobra de expansão pulmonar pode ser realizada em pacientes com TCE grave, estáveis hemodinamicamente e com PIC abaixo de 20 mmHg.
Delirium
Authors: Lôbo Rômulo Rebouças , Silva Filho Silvio R. B. , Lima Nereida K. C. , Ferriolli Eduardo , Moriguti Julio C. 
Published: June 2014

Delirium também conhecido como estado confusional agudo é uma alteração cognitiva definida por início agudo, curso flutuante, distúrbios da consciência, atenção, orientação, memória, pensamento, percepção e comportamento. É condição cada vez mais comum entre pacientes hospitalizados e acomete, preferencialmente, pacientes idosos e debilitados. Trata-se de emergência médica, já sendo comprovadas maiores taxas de mortalidade, maior tempo de internação e maiores índices de institucionalização quando do episódio de delirium.O mecanismo fisiopatológico ainda não está bem definido, sendo a alteração na neurotransmissão o mecanismo mais provável. A abordagem do paciente deve incluir a identificação de fatores predisponentes e precipitantes, com intervenções adequadas a cada um visando à resolução do quadro. Apresenta-se por alteração do nível de consciência, déficit de atenção e outros distúrbios da cognição, podendo se apresentar na forma hiperativa, hipoativa ou mista. Apesar de já estar bem definido, por diversas vezes passa despercebido aos profissionais de saúde. A principal medida na abordagem de delirium é a prevenção, e são necessárias medidas institucionais e treinamento dos profissionais de saúde. O tratamento não-farmacológico consiste em medidas que evitem os fatores responsáveis pelo desenvolvimento do delirium , sendo a primeira opção na abordagem inicial. O tratamento farmacológico se reserva aos pacientes com agitação importante, com risco de trauma físico, e que não apresentem resposta às medidas não-farmacológicas. Por sua frequência e importância como fator prognóstico, o delirium deve ser abordado de forma sistematizada, com a elaboração de fluxogramas de atendimento e definição de medidas uniformizadas para cada instituição. .
Effect of simulated resistance, fleeing, and use of force on standardized field sobriety testing
Authors: Ho Jeffrey , Dawes Donald , Nystrom Paul , Moore Johanna , Steinberg Lila , Tilton Annemarie , Miner James 
Published: June 2014

Introduction When a law enforcement officer (LEO) stops a suspect believed to be operating (a vehicle) while impaired (OWI), the suspect may resist or flee, and the LEO may respond with force. The suspect may then undergo a Standardized Field Sobriety Test (SFST) to gauge impairment. It is not known whether resistance, fleeing, or actions of force can create an inaccurate SFST result. We examined the effect of resistance, fleeing, and force on the SFST. Materials and Methods Human volunteers were prospectively randomized to have a SFST before and after one of five scenarios: (1) five-second conducted electrical weapon exposure; (2) 100-yard (91.4 m) sprint; (3) 45-second physical fight; (4) police dog bite with protective gear; and (5) Oleoresin Capsicum spray to the face with eyes shielded. The SFST was administered and graded by a qualified LEO. After the SFST, the volunteer entered their scenario and was then administered another SFST. Data were analyzed using descriptive statistics. SFST performance was compared before and after using chi-square tests. Results Fifty-seven subjects enrolled. Three received a single-point penalty during one component of the three-component SFST pre-scenario. No subject received a penalty point in any components of the SFST post-scenario (p = 0.08). Conclusions This is the first human study to examine the effects of physical resistance, flight, and use of force on the SFST result. We did not detect a difference in the performance of subjects taking the SFST before and after exposure to resistance, flight, or a simulated use of force.
Long-term T2 and Qualitative MRI Morphology After First-Generation Knee Autologous Chondrocyte Implantation
Authors: Salzmann Gian M. , Erdle Benjamin , Porichis Stella , Uhl Markus , Ghanem Nadir , Schmal Hagen , Kubosch David , Südkamp Norbert P. , Niemeyer Philipp 
Published: June 2014

Background: There are several reports on long-term clinical outcomes after autologous chondrocyte implantation (ACI) for knee cartilage defect treatment. Few published articles have evaluated defect quality using quantitative magnetic resonance (MR) imaging techniques. Purpose: To evaluate clinical outcomes and the quality of repair tissue (RT) after first-generation periosteum-covered ACI (ACI-P) using qualitative MR outcomes and T2-weighted relaxation times. Study Design: Case series; Level of evidence, 4. Methods: All patients (n = 86) who underwent knee joint ACI-P (from 1997 through 2001) with a postoperative follow-up of at least 10 years were invited for clinical and MR evaluation. Clinical outcomes analysis included pre- and postoperative Lysholm and numeric analog scale (NAS) for pain (10 = worst, 0 = best). Radiographic analysis included postoperative T2-weighted mapping of the RT, RT-associated regions, and healthy control cartilage; MOCART (magnetic resonance observation of cartilage repair tissue) score; a modified Knee Osteoarthritis Scoring System (mKOSS; 0 = best, 15 = worst) score; as well as numeric grading for subjective RT and whole knee joint evaluation (1 = best, 6 = worst). Results: A total of 70 patients (45 male, 25 female; mean age, 33.3 ± 10.2 years; 81% follow-up rate) with 82 defects were available for follow-up at an average 10.9 ± 1.1 years postoperatively, with MR analysis for 59 patients with 71 transplant sites (average defect size, 6.5 ± 4.0 cm2). Final Lysholm (71.0 ± 17.4) and NAS (7.2 ± 1.9) scores improved significantly when compared with preoperative scores (Lysholm: 42.0 ± 22.5; NAS: 2.1 ± 2.1; P < .01 for both). Average transplant T2 was 35.2 ± 11.3 ms and thereby significantly lower ( P = .005) when compared to the intraknee healthy femur T2 (39.7 ± 6.8 ms). The MOCART was 44.9 ± 23.6 and mKOSS was 4.8 ± 3.2. RT subjective grading was 3.3 ± 1.4, while it was 2.3 ± 0.7 for whole joint evaluation. The RT T2 significantly correlated with postoperative NAS ( P = .04; r = −0.28); it also correlated with the healthy femur T2 ( P = .004; r = 0.4). The MOCART significantly correlated with the mKOSS ( P < .001). Conclusion: The MRI outcome is imperfect in this collective of patients. There is only weak correlation of quantitative imaging data and clinical function. Qualitative imaging data are much better correlated to functional outcomes.
UK single centre experience of rare and atypical variant of castrate-resistant prostate cancer: Poorly differentiated neuroendocrine small-cell carcinoma
Authors: Hingorani Mohan , Morgan Russell , Robertson Andrew , Khafagy Richard , Hawkyard Simon 
Published: June 2014

Background: We report on the emergence of a rare and atypical variant of castrate-resistant prostate cancer (CRPC) that is characterised by transformation into poorly differentiated neuroendocrine small-cell carcinoma (NSCC). The existence of this variant was previously described in isolated case reports and small case-studies, but as yet there has been no UK series reported in the literature. Methods: Between January 2010 and January 2014, eight cases were presented in our local multi-disciplinary team meeting having a diagnosis of NSCC arising on a background of prostate cancer treated with androgen deprivation therapy. We performed a retrospective review of the clinical records of these patients, to identify the mode of presentation, diagnostic investigations, pathological characteristics, and subsequent treatment and survival outcomes. Results: The median patient age was 77 years (range, 68 – 84), with a median time interval of 25 months (range, 7 – 83) between the original diagnosis and subsequent transformation to NSCC. The median prostate-specific antigen (PSA) was 4 ng/ml, at presentation. Most patients presented with local progression, combined with high-volume and atypical sites of metastasis (e.g. brain, pancreas and penis). Patients developed a good initial response to platinum-based chemotherapy, but responses were short-lived and prognosis poor, with a median overall survival (OS) of 8 months. Conclusion: Prostate NSCC represents an atypical variant of CRPC with significant therapeutic and prognostic implications. Based on our observations, we have proposed a clinical algorithm for early diagnosis and appropriate management of these patients.
Inter-rater agreement, sensitivity, and specificity of the prone hip extension test and active straight leg raise test
Authors: Bruno Paul A , Millar David P , Goertzen Dale A 
Published: June 2014

Abstract
Background
Two clinical tests used to assess for neuromuscular control deficits in low back pain (LBP) patients are the prone hip extension (PHE) test and active straight leg raise (ASLR) test. For these tests, it has been suggested examiners classify patients as “positive” or “negative” based on the presence or absence (respectively) of specific “abnormal” lumbopelvic motion patterns. The inter-rater agreement of such a classification scheme has been reported for the PHE test, but not for the ASLR test. In addition, the sensitivity and specificity of such classification schemes have not been reported for either test. The primary objectives of the current study were to investigate: 1) the inter-rater agreement of the examiner-reported classification schemes for these two tests, and 2) the sensitivity and specificity of the classification schemes.

Methods
Thirty participants with LBP and 40 asymptomatic controls took part in this cross-sectional observational study. Participants performed 3–4 repetitions of each test whilst two examiners classified them as “positive” or “negative” based on the presence or absence (respectively) of specific “abnormal” lumbopelvic motion patterns. The inter-rater agreement (Kappa statistic), sensitivity (LBP patients), and specificity (controls) were calculated for each test.

Results
Both tests demonstrated substantial inter-rater agreement (PHE test: Kappa = 0.76, 95% CI = 0.57-0.95, p < 0.001; ASLR test: Kappa = 0.76, 95% CI = 0.57-0.96, p < 0.001). For the PHE test, the sensitivity was 0.18-0.27 and the specificity was 0.63-0.78; the odds ratio (OR) of “positive” classifications in the LBP group was 1.25 (95% CI = 0.58-2.72; Examiner 1) and 1.27 (95% CI = 0.52-3.12; Examiner 2). For the ASLR test, the sensitivity was 0.20-0.25 and the specificity was 0.84-0.86; the OR of “positive” classifications in the LBP group was 1.72 (95% CI = 0.75-3.95; Examiner 1) and 1.57 (95% CI = 0.64-3.85; Examiner 2).

Conclusion
Classification schemes for the PHE test and ASLR test based on the presence or absence of specific “abnormal” lumbopelvic motion patterns demonstrated substantial inter-rater agreement. However, additional investigation is required to further comment on the clinical usefulness of the motion patterns demonstrated by LBP patients during these tests as a diagnostic tool or treatment outcome.
Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations
Authors: Karagiannidis Christian , Kampe Kristin Aufm , Sipmann Fernando Suarez , Larsson Anders , Hedenstierna Goran , Windisch Wolfram , Mueller Thomas 
Published: June 2014

Abstract
Introduction
While non-invasive ventilation aimed at avoiding intubation has become the modality of choice to treat mild to moderate acute respiratory acidosis, many severely acidotic patients (pH <7.20) still need intubation. Extracorporeal veno-venous CO2 removal (ECCO2R) could prove to be an alternative. The present animal study tested in a systematic fashion technical requirements for successful ECCO2R in terms of cannula size, blood and sweep gas flow.

Methods
ECCO2R with a 0.98 m2 surface oxygenator was performed in six acidotic (pH <7.20) pigs using either a 14.5 French (Fr) or a 19Fr catheter, with sweep gas flow rates of 8 and 16 L/minute, respectively. During each experiment the blood flow was incrementally increased to a maximum of 400 mL/minute (14.5Fr catheter) and 1000 mL/minute (19Fr catheter).

Results
Amelioration of severe respiratory acidosis was only feasible when blood flow rates of 750 to 1000 mL/minute (19Fr catheter) were used. Maximal CO2-elimination was 146.1 ± 22.6 mL/minute, while pH increased from 7.13 ± 0.08 to 7.41 ± 0.07 (blood flow of 1000 mL/minute; sweep gas flow 16 L/minute). Accordingly, a sweep gas flow of 8 L/minute resulted in a maximal CO2-elimination rate of 138.0 ± 16.9 mL/minute. The 14.5Fr catheter allowed a maximum CO2 elimination rate of 77.9 mL/minute, which did not result in the normalization of pH.

Conclusions
Veno-venous ECCO2R may serve as a treatment option for severe respiratory acidosis. In this porcine model, ECCO2R was most effective when using blood flow rates ranging between 750 and 1000 mL/minute, while an increase in sweep gas flow from 8 to 16 L/minute had less impact on ECCO2R in this setting.
The Disposition Index Does Not Reflect β-Cell Function in IGT Subjects Treated With Pioglitazone
Authors: DeFronzo Ralph A. , Tripathy Devjit , Abdul-Ghani Muhammad , Musi Nicolas , Gastaldelli Amalia 
Published: June 2014

Abstract

Aims and Hypothesis:
The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity.

Methods:
A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years.

Results:
Pioglitazone reduced IGT conversion to diabetes by 72% (P &lt; .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia.

Conclusions:
These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.