Miracle-dz/UniFAR-FTUs huggingface dataset:
Study of dementia and cognitive decline accounting for selection by death

The purpose of this work is to develop statistical tools to study the general or the prediagnosis cognitive decline, while accounting for the selection by death and interval censoring. In cohort studies, the time-to-dementia-onset is interval-censored as the dementia status is assessed intermittently. This issue can lead to an under-estimation of the risk of dementia, due to the competing risk of death: subjects with dementia are at high risk to die and can thus die prior to the diagnosis visit. First, we propose a joint latent class illness-death model for longitudinal data correlated to an interval-censored time-to-event, competing with the time-to-death. This model is applied on the Paquid cohort to identify profiles of pre-dementia cognitive declines associated with different risks of dementia and death. Using this methodology, we compare dynamic prognostic models for dementia based on repeated measures of cognitive markers, accounting for interval censoring. Secondly, we conduct a simulation study to clarify the interpretation of maximum likelihood estimators of joint and mixed models as well as GEE estimators, frequently used to handle incomplete longitudinal data truncated by death. Maximum likelihood estimators target the individual change among the subjects currently alive. GEE estimators with independent working correlation matrix, weighted by the inverse probability to be observed given that the subject is alive, target the population-averaged change among the dynamic population of survivors. These results justify the use of joint models in dementia studies, which are promising statistical tools to better understand the natural history of dementia
Auditing Inequity

While much has been written about preparing educational leaders to lead for social justice, much less has been written about how to do so. This study is one of the first to analyze the reflections and written assignments of aspiring administrators to determine what they are currently thinking about poverty, race/ethnicity, and social justice leadership and how that thinking is shaped throughout one course. Results indicate that students were variable in their individual reflections, but that assignments, which required them to analyze the inequities in their schools and develop an implementation plan, led all of these aspiring administrators to seek to redress those inequities. The article discusses implications for other programs, which prepare educational leaders.
Protein design algorithms predict viable resistance to an experimental antifolate

Significance Computationally predicting drug resistance mutations early in the discovery phase would be an important breakthrough in drug development. The most meaningful predictions of target mutations will show reduced affinity for the drug while maintaining viability in the complex context of a cell. Here, the protein design algorithm K* in Osprey was used to predict a single-nucleotide polymorphism in the target dihydrofolate reductase that confers resistance to an experimental antifolate in the preclinical discovery phase. Excitingly, the mutation was also selected in bacteria under antifolate pressure, confirming the prediction of a viable molecular response to external stress. Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.
Retinal Pigment Epithelial Cells Suppress Phagolysosome Activation in Macrophages

Purpose The eye is an immune-privileged microenvironment that has adapted several mechanisms of immune regulation to prevent inflammation. One of these potential mechanisms is retinal pigment epithelial cells (RPE) altering phagocytosis in macrophages. Methods The conditioned media of RPE eyecups from eyes of healthy mice and mice with experimental autoimmune uveitis (EAU) were used to treat primary macrophage phagocytizing pHrodo bacterial bioparticles. In addition, the neuropeptides were depleted from the conditioned media of healthy RPE eyecups and used to treat phagocytizing macrophages. The conditioned media from healthy and EAU RPE eyecups were assayed for IL-6, and IL-6 was added to the healthy conditioned media, and neutralized in the EAU conditioned media. The macrophages were treated with the conditioned media and assayed for fluorescence. The macrophages were imaged, and the fluorescence intensity, relative to active phagolysosomes, was measured. Also, the macrophages were assayed using fluorescent viability dye staining. Results The conditioned media from healthy, but not from EAU RPE eyecups suppressed phagolysosome activation. Depletion of the neuropeptides alpha-melanocyte–stimulating hormone and neuropeptide Y from the healthy RPE eyecup conditioned media resulted in macrophage death. In the EAU RPE eyecup conditioned media was 0.96 ± 0.18 ng/mL of IL-6, and when neutralized the conditioned media suppressed phagolysosome activation. Conclusions The healthy RPE through soluble molecules, including alpha-melanocyte–stimulating hormone and neuropeptide Y, suppresses the activation of the phagolysosome in macrophages. In EAU, the IL-6 produced by the RPE promotes the activation of phagolysosomes in macrophages. These results demonstrate that under healthy conditions, RPE promotes an altered pathway of phagocytized material in macrophages with implications on antigen processing and clearance.
Space mapping: the state of the art

We review the space-mapping (SM) technique and the SM-based surrogate (modeling) concept and their applications in engineering design optimization. For the first time, we present a mathematical motivation and place SM into the context of classical optimization. The aim of SM is to achieve a satisfactory solution with a minimal number of computationally expensive "fine" model evaluations. SM procedures iteratively update and optimize surrogates based on a fast physically based "coarse" model. Proposed approaches to SM-based optimization include the original algorithm, the Broyden-based aggressive SM algorithm, various trust-region approaches, neural SM, and implicit SM. Parameter extraction is an essential SM subproblem. It is used to align the surrogate (enhanced coarse model) with the fine model. Different approaches to enhance uniqueness are suggested, including the recent gradient parameter-extraction approach. Novel physical illustrations are presented, including the cheese-cutting and wedge-cutting problems. Significant practical applications are reviewed.
A Systematic Review and Meta-Analysis of Diagnostic and Prognostic Serum Biomarkers of Colorectal Cancer

Background Our systematic review summarizes the evidence concerning the accuracy of serum diagnostic and prognostic tests for colorectal cancer (CRC). Methods The databases MEDLINE and EMBASE were searched iteratively to identify the relevant literature for serum markers of CRC published from 1950 to August 2012. The articles that provided adequate information to meet the requirements of the meta-analysis of diagnostic and prognostic markers were included. A 2-by-2 table of each diagnostic marker and its hazard ratio (HR) and the confidence interval (CI) of each prognostic marker was directly or indirectly extracted from the included papers, and the pooled sensitivity and specificity of the diagnostic marker and the pooled HR and the CI of the prognostic marker were subsequently calculated using the extracted data. Results In total, 104 papers related to the diagnostic markers and 49 papers related to the prognostic serum markers of CRC were collected, and only 19 of 92 diagnostic markers were investigated in more than two studies, whereas 21 out of 44 prognostic markers were included in two or more studies. All of the pooled sensitivities of the diagnostic markers with > = 3 repetitions were less than 50%, and the meta-analyses of the prognostic markers with more than 3 studies were performed, VEGF with highest (2.245, CI: 1.347–3.744) and MMP-7 with lowest (1.099, CI: 1.018–1.187)) pooled HRs are presented. Conclusions The quality of studies addressing the diagnostic and prognostic accuracy of the tests was poor, and the results were highly heterogeneous. The poor characteristics indicate that these tests are of little value for clinical practice.
Environmental novelty elicits a later theta phase of firing in CA1 but not subiculum

The mechanism supporting the role of the hippocampal formation in novelty detection remains controversial. A comparator function has been variously ascribed to CA1 or subiculum, whereas the theta rhythm has been suggested to separate neural firing into encoding and retrieval phases. We investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty‐induced plasticity in CA1. © 2009 Wiley‐Liss, Inc.
Active prediction of syntactic information during sentence processing

We describe an eye-tracking experiment that tested the effect of syntactic predictability on skipping rates during reading. We found that plural noun phrases were skipped more often than singular noun phrases, in syntactic contexts which induced a high expectation for a plural. We interpret this effect as evidence that the plural noun phrase has been predicted ahead of time. The results indicate that the examination of skipping rates might be a useful tool for the investigation of syntactic prediction effects.
Very long-term prognosis of patients with malignant uveal melanoma.

PURPOSE To investigate the very long-term prognosis of patients with uveal melanoma and the clinical characteristics influencing it. METHODS Charts, registry data, and histopathologic specimens of 289 consecutive patients with choroidal and ciliary body melanoma treated in the district of the Helsinki University Central Hospital, Finland, between 1962 and 1981 were audited. Definitions for coding the cause of death were adapted from the Collaborative Ocular Melanoma Study (COMS). Competing risks were taken into account by using cumulative incidence analysis and competing risks regression. RESULTS Of the 289 patients treated, 239 were deceased at the end of follow-up. The audited cause of death was uveal melanoma in 145 (61%) of them. The median follow-up of the 50 survivors was 28 years. The original histopathologic diagnosis of metastasis and second cancer was correct in 91% of all specimens, but immunohistochemical reassessment changed 10% of biopsy and 7% of autopsy diagnoses. Of 45 positive autopsies, 18% were performed without suspicion of melanoma. Uveal melanoma-related mortality was 31% (95% confidence interval [CI], 26-37) by 5 years, 45% (95% CI, 40-51) by 15 years, 49% (95% CI, 43-55) by 25 years, and 52% (95% CI, 45-58) by 35 years, according to cumulative incidence analysis. Of patients who died of uveal melanoma, 62%, 90%, 98%, and 100% did so within 5, 15, 25, and 35 years, respectively. Between 15 and 35 years, 20% to 33% of deaths were still due to uveal melanoma. By competing risks regression analysis, the hazard ratio was 1.08 (P=0.0012) for each millimeter increase in tumor diameter, 2.27 (P=0.0076) for extraocular growth, and 1.89 (P=0.0011) for ciliary body involvement. CONCLUSIONS Metastatic uveal melanoma was the leading single cause of death throughout the study. Cumulative incidences provide a sound basis for patient counseling and design of trials.
Application-Aware diagnosis of runtime hardware faults

Extreme technology scaling in silicon devices drastically affects reliability, particularly because of runtime failures induced by transistor wearout. Current online testing mechanisms focus on testing all components in a microprocessor, including hardware that has not been exercised, and thus have high performance penalties. We propose a hybrid hardware/software online testing solution where components that are heavily utilized by the software application are tested more thoroughly and frequently. Thus, our online testing approach focuses on the processor units that affect application correctness the most, and it achieves high coverage while incurring minimal performance overhead. We also introduce a new metric, Application-Aware Fault Coverage, measuring a test's capability to detect faults that might have corrupted the state or the output of an application. Test coverage is further improved through the insertion of observation points that augment the coverage of the testing system. By evaluating our technique on a Sun OpenSPARC T1, we show that our solution maintains high Application-Aware Fault Coverage while reducing the performance overhead of online testing by more than a factor of 2 when compared to solutions oblivious to application's behavior. Specifically, we found that our solution can achieve 95% fault coverage while maintaining a minimal performance overhead (1.3%) and area impact (0.4%).
A Probabilistic Approach to the Analysis of Program Execution Time

Acknowledgment Bismillahirrahmanirrahim alhamdulillahirabbil'alamin. This thesis is the result of six months training performed at the TNO-TPD 1 Institute of Applied Physics during the months of October 1997 to March 1998 as well as a follow up period at Delft University of Technology (TU Delft) from April to July 1998. The work was aimed at the development of a probabilistic approach to the analysis of program execution time. I am grateful to ir. T. Vogel, my supervisor at TPD. Further, all people at TPD for ooering a pleasant and stimulating working environment. I am extremely grateful to dr. ir. A.J.C. van Gemund for being my goeroe, being indefatigable in continuously discussing, rereading and commenting on all my work. The existence of a better supervisor is quite unthinkable. Most of all I would like to thank to my wife, Henny Marlina, for her love and support. Abstract We present a new approach to the performance prediction of parallel programs that provides information on the distribution of execution times when considering a large space of input data sets. The research aims to extend low-cost performance analysis techniques by accounting for the stochastic behavior of system parameters. Current analysis techniques are based on path analysis with the assumption of deterministic task times (mean values) instead of accounting for variance. Most of the system model parameters, however, are stochastic rather than deterministic due to data dependency in programs, for example in terms of branches and loop bounds, as well as due to various other probabilistic model abstractions. The approach is based on moments representations of distribution. We present a low-cost algorithm that computes the moments of the program execution time based on the moments associated with branching, loop bounds, and basic blocks. The novelty of the analysis technique is the combination between the general validity of the stochastic analysis with moment representations and accounting for the correlation of control constructs in the prediction of execution times. The approach has been successfully tested on four example programs.
Human epidermal growth factor enhances healing of diabetic foot ulcers.

OBJECTIVE To study the healing effect of recombinant human epidermal growth factor (hEGF) on diabetic foot ulcers. RESEARCH DESIGN AND METHODS A total of 127 consecutive patients were screened and 61 diabetic subjects were recruited into this double-blind randomized controlled study. Predetermined criteria were used for diagnosis and classification of the diabetic wound. The patients were randomized into three groups. All patients attended our Diabetes Ambulatory Care Center every other week for joint consultation with the diabetologist and the podiatrist. Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks. RESULTS Final data were obtained from 61 patients randomly assigned into three groups. The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and comorbidities were comparable within groups, except that group 3 had more female patients. Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2 (0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7 had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02% (wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12 weeks and increased the rate of healing compared with the other treatments (log-rank test, P = 0.0003). CONCLUSIONS Our data support the contention that application of hEGF-containing cream, in addition to good foot care from a multidisciplinary team, significantly enhances diabetic foot ulcer wound healing and reduces the healing time.
Practical issues with the timing analysis of the Controller Area Network

The Controller Area Network (CAN) bus is widely used and has been studied in several research works to determine the worst-case response time of messages. More results are being added to study systems that are not constructed according to the ideal behavior of the message queuing and CAN controller assumed in the past. In this paper, we provide an assessment on the practical relevance of several of those results. We also present theory and empirical studies on the relative importance of several implementation issues that are quite common in real systems and further deviate from the ideal behavior. In addition, we propose a heuristic for the design of multiple software queues when using TxObjects without preemption, and derive an upper bound on the worst case response time when message output at the CAN driver is polling based.
C, N, O in λ Boo stars and in composite spectra

The selective abundance of C, N, O (almost solar) with respect to that of other elements (underabundant) in λ Boo stars has been interpreted as a characteristic peculiarity of these objects, when considered as single stars. We show here that a similar selective abundance is predicted from the composite spectra resulting from two unresolved stars in the same temperature range as the λ Boo stars.
A New Multiple-Round DOR Routing for 2D Network-on-Chip Meshes

The Network-on-Chip (NoC) meshes are limited by the reliability constraint, which impels us to exploit the fault tolerant routing. Particularly, one of the main design issues is minimizing the loss of non-faulty routers at the presence of faults. To address that problem, we propose a new fault tolerant routing, which has the following two distinct advantages: First, it keeps a network deadlock-free by utilizing restricted intermediate nodes rather than adding virtual channels (VC). This characteristic leads to an area-efficient router. Second, in the proposed routing algorithm, the rounds of DOR are not limited by the number of VC’s anymore. As a consequence, the number of sacrificed non-faulty routers is significantly reduced. We demonstrate above advantages through extensive simulations. The experimental results show that under the limitation of VC’s, the proposed routing algorithm always sacrifices the minimal number of non-faulty routers compared to previous solutions.
Inter-Annual Variations of Methane Emission from an Open Fen on the Qinghai-Tibetan Plateau: A Three-Year Study

The study aimed to understand the inter-annual variations of methane (CH4) emissions from an open fen on the Qinghai-Tibetan Plateau (QTP) from 2005 to 2007. The weighted mean CH4 emission rate was 8.37±11.32 mg CH4 m−2 h−1 during the summers from 2005 to 2007, falling in the range of CH4 fluxes reported by other studies, with significant inter-annual and spatial variations. The CH4 emissions of the year of 2006 (2.11±3.48 mg CH4 m−2 h−1) were 82% lower than the mean value of the years 2005 and 2007 (13.91±17.80 mg CH4 m−2 h−1 and 9.44±14.32 mg CH4 m−2 h−1, respectively), responding to the inter-annual changes of standing water depths during the growing season of the three years. Significant drawdown of standing water depth is believed to cause such significant reduction in CH4 emissions from wetlands in the year 2006, probably through changing the methanogen composition and decreasing its community size as well as activating methanotrophs to enhance CH4 oxidation. Our results are helpful to understand the inter-annual variations of CH4 emission and provide a more reasonable regional budget of CH4 emission from wetlands on the QTP and even for world-wide natural wetlands under climate change.