bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality
Authors: Anyona Samuel B. , Kempaiah Prakasha , Raballah Evans , Ouma Collins , Were Tom , Davenport Gregory C. , Konah Stephen N. , Vulule John M. , Hittner James B. , Gichuki Charity W. , Ong'echa John M. , Perkins Douglas J. 
Published: October 2011

ABSTRACTSevere malarial anemia (SMA) is a leading cause of morbidity and mortality in children residing in regions wherePlasmodium falciparumtransmission is holoendemic. Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (−137G→C [rs187238] and −607C→A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes/haplotypes, SMA (hemoglobin [Hb], <5.0 g/dl], and longitudinal clinical outcomes were then investigated in Kenyan children (n= 719). Multivariate logistic regression analyses controlling for age, gender, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the −607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90],P= 0.031) in children with acute infection. In contrast, carriers of the −137G/−607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05],P= 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (ρ = −0.293,P= 0.010) and that carriers of the “susceptible” GC haplotype had elevated IL-18 transcripts (P= 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (∼1% frequency) had 5.76 times higher mortality than noncarriers (P= 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality.
Checksum-Aware Fuzzing Combined with Dynamic Taint Analysis and Symbolic Execution
Authors: Wang Tielei , Wei Tao , Gu Guofei , Zou Wei 
Published: October 2011

Fuzz testing has proven successful in finding security vulnerabilities in large programs. However, traditional fuzz testing tools have a well-known common drawback: they are ineffective if most generated inputs are rejected at the early stage of program running, especially when target programs employ checksum mechanisms to verify the integrity of inputs. This article presents TaintScope, an automatic fuzzing system using dynamic taint analysis and symbolic execution techniques, to tackle the above problem. TaintScope has several novel features: (1) TaintScope is a checksum-aware fuzzing tool. It can identify checksum fields in inputs, accurately locate checksum-based integrity checks by using branch profiling techniques, and bypass such checks via control flow alteration. Furthermore, it can fix checksum values in generated inputs using combined concrete and symbolic execution techniques. (2) TaintScope is a taint-based fuzzing tool working at the x86 binary level. Based on fine-grained dynamic taint tracing, TaintScope identifies the “hot bytes” in a well-formed input that are used in security-sensitive operations (e.g., invoking system/library calls), and then focuses on modifying such bytes with random or boundary values. (3) TaintScope is also a symbolic-execution-based fuzzing tool. It can symbolically evaluate a trace, reason about all possible values that can execute the trace, and then detect potential vulnerabilities on the trace.
We evaluate TaintScope on a number of large real-world applications. Experimental results show that TaintScope can accurately locate the checksum checks in programs and dramatically improve the effectiveness of fuzz testing. TaintScope has already found 30 previously unknown vulnerabilities in several widely used applications, including Adobe Acrobat, Flash Player, Google Picasa, and Microsoft Paint. Most of these severe vulnerabilities have been confirmed by Secunia and oCERT, and assigned CVE identifiers (such as CVE-2009-1882, CVE-2009-2688). Vendor patches have been released or are in preparation based on our reports.
Using Network Calculus to compute end-to-end delays in SpaceWire networks
Authors: Ferrandiz Thomas , Frances Fabrice , Fraboul Christian 
Published: October 2011

The SpaceWire network standard is promoted by the ESA and is scheduled to be used as the sole on-board network for future satellites. This network uses a wormhole routing mechanism that can lead to packet blocking in routers and consequently to variable end-to-end delays. As the network will be shared by real-time and non real-time traffic, network designers require a tool to check that temporal constraints are verified for all the critical messages.
Network Calculus can be used for evaluating worst-case end-to-end delays. However, we first have to model SpaceWire components through the definition of service curves. In this paper, we propose a new Network Calculus element that we call the Wormhole Section. This element allows us to better model a wormhole network than the usual multiplexer and demultiplexer elements used in the context of usual Store-and-Forward networks.
70 km/h Speed Limits on Former 90 km/h Roads
Authors: Jongen Ellen M. M. , Brijs Kris , Mollu Kristof , Brijs Tom , Wets Geert 
Published: October 2011

Objective: It was investigated how speed limit repetition and distraction affect drivers’ speed management throughout a road section where the imposed speed limit is not in accordance (too low) with road design. Background: It is not clear how driving speed evolves and to what degree speed limit repetition is necessary on roads where the imposed speed limit is not in accordance (too low) with road design. It is furthermore of interest how all these factors are influenced by driver distraction. Method: In a driving simulator, 47 volunteers completed one trip with and without distraction. Within each trip, three configurations were presented: speed limit sign repetition after every intersection, repetition only in the middle of a segment, or no repetition. Results: Distraction lowered driving speed. Speed management varied depending on speed limit repetition. The speed limit was exceeded more often when speed limit signs were repeated less frequently. When drivers were not reminded of the limit, speed linearly increased throughout the segment. In all three configurations, speed increased toward the end of the segment, but this increase was largest when there had been no repetition at all of the speed limit. Conclusion: In low-demanding road designs that allow drivers to exceed the speed limit, limit repetition is necessary. Frequent repetition may be preferred, as speed management was most homogenous in that case. Application: The proposed analysis of speed management throughout a section increases our understanding of how speed evolves and thereby shows where repetition of the speed limit is necessary.
Autologous Chondrocyte Implantation for Treatment of Cartilage Defects of the Knee
Authors: Jungmann Pia M. , Salzmann Gian M. , Schmal Hagen , Pestka Jan M. , Südkamp Norbert P. , Niemeyer Philipp 
Published: October 2011

Background: Autologous chondrocyte implantation (ACI) is a well-established treatment option for isolated cartilage defects of the knee joint, providing satisfying outcome. However, cases of treatment failure with the need for surgical reintervention are reported; typical patient’s individual and environmental risk factors have previously not been described. Hypothesis: The need for reintervention after ACI is associated with specific preoperative detectable individual risk factors. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 413 patients following ACI (first, second, and third generation) were filtered for those who required revision surgery during their follow-up time (2-11.8 years). Factors were analyzed that might have significant effects on increased revision rate. Using preoperatively collected data, all patients were grouped according to 12 standard prognostic factors. Apart from odds ratio and Pearson χ2 test, statistical analysis of risk factors was performed with multivariate binary logistic regression models and Cox regression, the method of choice for survival time data. Results: After a follow-up of 4.4 ± 0.9 years (limited to 5 years), a total of 88 patients (21.3%) had undergone surgical revision. The time to revision surgery was 1.8 ± 1.1 years. Four prognostic factors associated with a significantly higher risk for reintervention were detected: (1) female gender (Cox survival fit: P = .033), (2) previous surgeries of the affected joint ( P = .002), (3) previous bone marrow stimulation ( P = .041), and (4) periosteum patch–covered ACI ( P = .028). An influence of patient age, body mass index (BMI), defect number, defect size, lesion origin, lesion location, parallel treatment, or smoking on the risk for reintervention could not be observed. Conclusion: The study identifies clear facts that significantly increase the risk of revision surgery. These facts can be easily obtained preoperatively and may be taken into consideration when indicating ACI.
Effect of time of day on walking capacity and self-reported fatigue in persons with multiple sclerosis: a multi-center trial
Authors: Feys P , Gijbels D , Romberg A , Santoyo C , Gebara B , de Noordhout B Maertens , Knuts K , Béthoux F , de Groot V , Vaney C , Dalgas U 
Published: October 2011

Background: Many persons with multiple sclerosis (PwMS) report increased fatigue in the afternoon and evening compared with the morning. It is commonly accepted that physical capacity also decreases as time of day progresses, potentially influencing the outcomes of testing. Objective: The objective of this article was to determine whether self-reported fatigue level and walking capacity are influenced by time of day in PwMS. Methods: A total of 102 PwMS from 8 centers in 5 countries, with a diverse level of ambulatory dysfunction (Expanded Disability Status Scale [EDSS] <6.5), participated. Patients performed walking capacity tests and reported fatigue level at three different time points (morning, noon, afternoon) during 1 day. Walking capacity was measured with the 6-Minute Walk Test (6MWT) and the 10-m walk test performed at usual and fastest speed. Self-reported fatigue was measured by the Rochester Fatigue Diary (RFD). Subgroups with mild (EDSS 1.5–4.0, n = 53) and moderate (EDSS 4.5–6.5, n = 49) ambulatory dysfunction were formed, as changes during the day were hypothesized to depend on disability status. Results: Subgroups had different degree of ambulatory dysfunction ( p < 0.001) but reported similar fatigue levels. Although RFD scores were affected by time of day with significant differences between morning and noon/afternoon ( p < 0.0001), no changes in walking capacity were found in any subgroup. Additional analyses on subgroups distinguished by diurnal change in self-reported fatigue failed to reveal analogous changes in walking capacity. Conclusions: Testing of walking capacity is unaffected by time of day, despite changes in subjective fatigue.
Multivariable Model for Time to First Treatment in Patients With Chronic Lymphocytic Leukemia
Authors: Wierda William G. , O'Brien Susan , Wang Xuemei , Faderl Stefan , Ferrajoli Alessandra , Do Kim-Anh , Garcia-Manero Guillermo , Cortes Jorge , Thomas Deborah , Koller Charles A. , Burger Jan A. , Lerner Susan , Schlette Ellen , Abruzzo Lynne , Kantarjian Hagop M. , Keating Michael J. 
Published: October 2011

Purpose The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL. Patients and Methods Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram—a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment. Results There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status. Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials.
Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations
Authors: King Kathryn S. , Prodanov Tamara , Kantorovich Vitaly , Fojo Tito , Hewitt Jacqueline K. , Zacharin Margaret , Wesley Robert , Lodish Maya , Raygada Margarita , Gimenez-Roqueplo Anne-Paule , McCormack Shana , Eisenhofer Graeme , Milosevic Dragana , Kebebew Electron , Stratakis Constantine A. , Pacak Karel 
Published: October 2011

Purpose To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. Patients and Methods From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Results Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. Conclusion The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.
Gemcitabine Plusnab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial
Authors: Von Hoff Daniel D. , Ramanathan Ramesh K. , Borad Mitesh J. , Laheru Daniel A. , Smith Lon S. , Wood Tina E. , Korn Ronald L. , Desai Neil , Trieu Vuong , Iglesias Jose L. , Zhang Hui , Soon-Shiong Patrick , Shi Tao , Rajeshkumar N.V. , Maitra Anirban , Hidalgo Manuel 
Published: October 2011

PurposeThe trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.Patients and MethodsPatients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m2nab-paclitaxel followed by gemcitabine 1,000 mg/m2on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.ResultsA total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m2, respectively. The MTD was 1,000 mg/m2of gemcitabine plus 125 mg/m2of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.ConclusionThe regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Incidence and Outcome of Male Breast Cancer: An International Population-Based Study
Authors: Miao Hui , Verkooijen Helena M. , Chia Kee-Seng , Bouchardy Christine , Pukkala Eero , Larønningen Siri , Mellemkjær Lene , Czene Kamila , Hartman Mikael 
Published: October 2011

Purpose Male breast cancer is a rare disease with an incidence rate less than 1% of that of female breast cancer. Given its low incidence, few studies have assessed risk and prognosis. Methods This population-based study, including 459,846 women and 2,665 men diagnosed with breast cancer in Denmark, Finland, Geneva, Norway, Singapore, and Sweden over the last 40 years, compares trends in incidence, relative survival, and relative excess mortality between the sexes. Results World standardized incidence rates of breast cancer were 66.7 per 105 person-years in women and 0.40 per 105 person-years in men. Women were diagnosed at a younger median age (61.7 years) than men (69.6 years). Male patients had a poorer 5-year relative survival ratio than women (0.72 [95% CI, 0.70 to 0.75] v 0.78 [95% CI, 0.78 to 0.78], respectively), corresponding to a relative excess risk (RER) of 1.27 (95% CI, 1.13 to 1.42). However, after adjustment for age and year of diagnosis, stage, and treatment, male patients had a significantly better relative survival from breast cancer than female patients (RER, 0.78; 95% CI, 0.62 to 0.97). Conclusion Male patients with breast cancer have later onset of disease and more advanced disease than female patients. Male patients with breast cancer have lower risk of death from breast cancer than comparable female patients.
Predictive Variables for the Successful Treatment of Trigeminal Neuralgia With Gamma Knife Radiosurgery
Authors: Marshall Kopriva , Chan Michael D. , McCoy Thomas P. , Aubuchon Adam C. , Bourland J. Daniel , McMullen Kevin P. , deGuzman Allan F. , Munley Michael T. , Shaw Edward G. , Tatter Stephen B. , Ellis Thomas L. 
Published: October 2011

Abstract

Background:
Gamma Knife radiosurgery (GKRS) has been reported to be an effective modality to treat trigeminal neuralgia.

Objective:
To determine predictive factors for the successful treatment of trigeminal neuralgia with GKRS.

Methods:
Between 1999 and 2008, 777 GKRS procedures for patients with trigeminal neuralgia were performed at our institution. Evaluable follow-up data were obtained for 448 patients. Median follow-up time was 20.9 months (range, 3–86 months). The mean maximum prescribed dose was 88 Gy (range, 80–97 Gy). Dosimetric variables recorded included dorsal root entry zone dose, pons maximum dose, dose to the petrous dural ridge, and cisternal nerve length.

Results:
By 3 months after GKRS, 86% of patients achieved Barrow Neurologic Institute I to III pain scores, with 43% of patients achieving a Barrow Neurologic Institute I pain score. Twenty-six percent of patients reported posttreatment facial numbness; 28% of patients reported a post-GKRS procedure for relapsed pain, and median time to next procedure was 4.4 years. Multivariate analysis revealed that the development of postsurgical numbness (odds ratio [OR], 2.76; P = .006) was the dominant factor predictive of efficacy. Longer cisternal nerve length (OR, 0.85; P = .005), prior radiofrequency ablation (OR, 0.35; P = .028), and diabetes mellitus (OR, 0.38; P = .013) predicted decreased efficacy. The mean dose delivered to the dorsal root entry zone dose in patients who developed facial numbness (57.6 Gy) was more than the mean dose (47.3 Gy) given to patients who did not develop numbness (P = .02).

Conclusion:
The development of post-GKRS facial numbness is a dominant factor that predicts for efficacy of GKRS. History of diabetes mellitus or previous radio-frequency ablation may portend worsened outcome.