UC Irvine Health

This paper describes a discriminatively trained, multiscale, deformable part model for object detection. Our system achieves a two-fold improvement in average precision over the best performance in the 2006 PASCAL person detection challenge. It also outperforms the best results in the 2007 challenge in ten out of twenty categories. The system relies heavily on deformable parts. While deformable part models have become quite popular, their value had not been demonstrated on difficult benchmarks such as the PASCAL challenge. Our system also relies heavily on new methods for discriminative training. We combine a margin-sensitive approach for data mining hard negative examples with a formalism we call latent SVM. A latent SVM, like a hidden CRF, leads to a non-convex training problem. However, a latent SVM is semi-convex and the training problem becomes convex once latent information is specified for the positive examples. We believe that our training methods will eventually make possible the effective use of more latent information such as hierarchical (grammar) models and models involving latent three dimensional pose.

Introduction Contracting A Modern Dilemma Contract Making The Contract Makers Contemporary Contracts Violating the Contract Changing the Contract Business Strategy and Contracts Trends in the New Social Contract

We introduce the author-topic model, a generative model for documents that extends Latent Dirichlet Allocation (LDA; Blei, Ng, & Jordan, 2003) to include authorship information. Each author is associated with a multinomial distribution over topics and each topic is associated with a multinomial distribution over words. A document with multiple authors is modeled as a distribution over topics that is a mixture of the distributions associated with the authors. We apply the model to a collection of 1,700 NIPS conference papers and 160,000 CiteSeer abstracts. Exact inference is intractable for these datasets and we use Gibbs sampling to estimate the topic and author distributions. We compare the performance with two other generative models for documents, which are special cases of the author-topic model: LDA (a topic model) and a simple author model in which each author is associated with a distribution over words rather than a distribution over topics. We show topics recovered by the author-topic model, and demonstrate applications to computing similarity between authors and entropy of author output.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Two modeling approaches are commonly used to estimate the associations between neighborhood characteristics and individual-level health outcomes in multilevel studies (subjects within neighborhoods). Random effects models (or mixed models) use maximum likelihood estimation. Population average models typically use a generalized estimating equation (GEE) approach. These methods are used in place of basic regression approaches because the health of residents in the same neighborhood may be correlated, thus violating independence assumptions made by traditional regression procedures. This violation is particularly relevant to estimates of the variability of estimates. Though the literature appears to favor the mixed-model approach, little theoretical guidance has been offered to justify this choice. In this paper, we review the assumptions behind the estimates and inference provided by these 2 approaches. We propose a perspective that treats regression models for what they are in most circumstances: reasonable approximations of some true underlying relationship. We argue in general that mixed models involve unverifiable assumptions on the data-generating distribution, which lead to potentially misleading estimates and biased inference. We conclude that the estimation-equation approach of population average models provides a more useful approximation of the truth.

Self-adaptive software requires high dependability robustness, adaptability, and availability. The article describes an infrastructure supporting two simultaneous processes in self-adaptive software: system evolution, the consistent application of change over time, and system adaptation, the cycle of detecting changing circumstances and planning and deploying responsive modifications.

Abstract We present cosmological results from the measurement of baryon acoustic oscillations (BAO) in galaxy, quasar and Lyman- α forest tracers from the first year of observations from the Dark Energy Spectroscopic Instrument (DESI), to be released in the DESI Data Release 1. DESI BAO provide robust measurements of the transverse comoving distance and Hubble rate, or their combination, relative to the sound horizon, in seven redshift bins from over 6 million extragalactic objects in the redshift range 0.1 < z < 4.2. To mitigate confirmation bias, a blind analysis was implemented to measure the BAO scales. DESI BAO data alone are consistent with the standard flat ΛCDM cosmological model with a matter density Ω m =0.295±0.015. Paired with a baryon density prior from Big Bang Nucleosynthesis and the robustly measured acoustic angular scale from the cosmic microwave background (CMB), DESI requires H 0 =(68.52±0.62) km s -1 Mpc -1 . In conjunction with CMB anisotropies from Planck and CMB lensing data from Planck and ACT, we find Ω m =0.307± 0.005 and H 0 =(67.97±0.38) km s -1 Mpc -1 . Extending the baseline model with a constant dark energy equation of state parameter w , DESI BAO alone require w =-0.99 +0.15 -0.13 . In models with a time-varying dark energy equation of state parametrised by w 0 and w a , combinations of DESI with CMB or with type Ia supernovae (SN Ia) individually prefer w 0 > -1 and w a < 0. This preference is 2.6 σ for the DESI+CMB combination, and persists or grows when SN Ia are added in, giving results discrepant with the ΛCDM model at the 2.5 σ , 3.5 σ or 3.9 σ levels for the addition of the Pantheon+, Union3, or DES-SN5YR supernova datasets respectively. For the flat ΛCDM model with the sum of neutrino mass ∑ m ν free, combining the DESI and CMB data yields an upper limit ∑ m ν < 0.072 (0.113) eV at 95% confidence for a ∑ m ν > 0 (∑ m ν > 0.059) eV prior. These neutrino-mass constraints are substantially relaxed if the background dynamics are allowed to deviate from flat ΛCDM.

BACKGROUND: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

The Hypertext Transfer Protocol (HTTP) is an application-level protocol with the lightness and speed necessary for distributed, collaborative, hypermedia information systems. It is a generic, stateless, object-oriented protocol which can be used for many tasks, such as name servers and distributed object management systems, through extension of its request methods (commands). A feature of HTTP is the typing of data representation, allowing systems to be built independently of the data being transferred.

Abstract Horizon-scale images of black holes (BHs) and their shadows have opened an unprecedented window onto tests of gravity and fundamental physics in the strong-field regime. We consider a wide range of well-motivated deviations from classical general relativity (GR) BH solutions, and constrain them using the Event Horizon Telescope (EHT) observations of Sagittarius A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msup> <mml:mi/> <mml:mo>∗</mml:mo> </mml:msup> </mml:math> (Sgr A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msup> <mml:mi> </mml:mi> <mml:mo>∗</mml:mo> </mml:msup> </mml:math> ), connecting the size of the bright ring of emission to that of the underlying BH shadow and exploiting high-precision measurements of Sgr A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msup> <mml:mi> </mml:mi> <mml:mo>∗</mml:mo> </mml:msup> </mml:math> ’s mass-to-distance ratio. The scenarios we consider, and whose fundamental parameters we constrain, include various regular BHs, string-inspired space-times, violations of the no-hair theorem driven by additional fields, alternative theories of gravity, novel fundamental physics frameworks, and BH mimickers including well-motivated wormhole and naked singularity space-times. We demonstrate that the EHT image of Sgr A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msup> <mml:mi/> <mml:mo>∗</mml:mo> </mml:msup> </mml:math> places particularly stringent constraints on models predicting a shadow size larger than that of a Schwarzschild BH of a given mass, with the resulting limits in some cases surpassing cosmological ones. Our results are among the first tests of fundamental physics from the shadow of Sgr A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msup> <mml:mi/> <mml:mo>∗</mml:mo> </mml:msup> </mml:math> and, while the latter appears to be in excellent agreement with the predictions of GR, we have shown that a number of well-motivated alternative scenarios, including BH mimickers, are far from being ruled out at present.

Why do successful companies let down their corporate walls, exposing their organizations and strategies to competitors? The answer, according to Joseph Badaracco is that corporations enter into strategic alliances to capitalize on knowledge: migratory knowledge, often technical in nature, which can be transferred easily between people or organizations in a formula or product, and embedded knowledge, which defines how a particular company organizes itself to do business. In today's business environment companies need to utilize each type of knowledge to sustain their competitive advantage. The challenge for today's manager is to balance the opportunities offered by open boundaries and free flowing information against the need to protect the corporations's unique advantages. Managing strategic alliances effectively will determine corporate success in the years ahead.

PURPOSE To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC). METHODS ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti–vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti–epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti–vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E–mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Abstract The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer’s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype ( p = 7.18 × 10 −4 ) or temporal stage ( p = 3.96 × 10 −5 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.

INTRODUCTION: Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency defined as decreased serum level of IgA in the presence of normal levels of other immunoglobulin isotypes. Most individuals with IgA deficiency are asymptomatic and identified coincidentally. However, some patients may present with recurrent infections of the respiratory and gastrointestinal tracts, allergic disorders, and autoimmune manifestations. IGA AND ITS FUNCTIONS: Although IgA is the most abundant antibody isotype produced in the body, its functions are not clearly understood. Subclass IgA1 in monomeric form is mainly found in the blood circulation, whereas subclass IgA2 in dimeric form is the dominant immunoglobulin in mucosal secretions. Secretory IgA appears to have prime importance in immune exclusion of pathogenic microorganisms and maintenance of intestinal homeostasis. Despite this critical role, there may be some compensatory mechanisms that would prevent disease manifestations in some IgA-deficient individuals. PATHOGENESIS: In IgA deficiency, a maturation defect in B cells to produce IgA is commonly observed. Alterations in transmembrane activator and calcium modulator and cyclophilin ligand interactor gene appear to act as disease-modifying mutations in both IgA deficiency and common variable immunodeficiency, two diseases which probably lie in the same spectrum. Certain major histocompatibility complex haplotypes have been associated with susceptibility to IgA deficiency. CONCLUSION: The genetic basis of IgA deficiency remains to be clarified. Better understanding of the production and function of IgA is essential in elucidating the disease mechanism in IgA deficiency.

An increasing number of wireless applications rely on GPS signals for localization, navigation, and time synchronization. However, civilian GPS signals are known to be susceptible to spoofing attacks which make GPS receivers in range believe that they reside at locations different than their real physical locations. In this paper, we investigate the requirements for successful GPS spoofing attacks on individuals and groups of victims with civilian or military GPS receivers. In particular, we are interested in identifying from which locations and with which precision the attacker needs to generate its signals in order to successfully spoof the receivers. We will show, for example, that any number of receivers can easily be spoofed to one arbitrary location; however, the attacker is restricted to only few transmission locations when spoofing a group of receivers while preserving their constellation. In addition, we investigate the practical aspects of a satellite-lock takeover, in which a victim receives spoofed signals after first being locked on to legitimate GPS signals. Using a civilian GPS signal generator, we perform a set of experiments and find the minimal precision of the attacker's spoofing signals required for covert satellite-lock takeover.

Secure group communication is an increasingly popular research area having received much attention in recent years. The fundamental challenge revolves around secure and efficient group key management. While centralized methods are often appropriate for key distribution in large groups, many collaborative group settings require distributed key agreement techniques. This work investigates a novel approach to group key agreement by blending binary key trees with Diffie-Hellman key exchange. The resultant protocol suite is very simple, secure and fault-tolerant. Moreover, its efficiency surpasses that of prior art.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

OBJECTIVE: To evaluate the clinical and pathological features of a subgroup of patients with Alzheimer disease (AD) who exhibited early and disproportionately severe impairments on tests of frontal lobe functioning. We hypothesized that these patients would exhibit a greater degree of either neurofibrillary tangle (NFT) or senile plaque pathology in the frontal lobes than would patients with typical AD. DESIGN AND OUTCOME MEASURES: We examined the neuropsychological profiles and senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in 3 patients with AD who exhibited disproportionate frontal impairments during early stages of dementia (frontal AD) and 3 matched patients with typical AD (typical AD). RESULTS: Compared with the typical AD group, the frontal AD group performed significantly worse on 2 tests of frontal lobe functioning and on the Wechsler Adult Intelligence Scale-Revised Block Design test. No significant group differences were found on other tests. Analysis of brain tissue samples demonstrated that, despite comparable entorhinal, temporal, and parietal NFT loads, the frontal AD group showed a significantly higher NFT load in the frontal cortex than the typical AD group. Senile plaque pathology in the frontal and entorhinal cortices did not differentiate the 2 groups. CONCLUSIONS: We identified a subgroup of patients with pathologically confirmed AD who presented in the early stages of dementia with disproportionate impairments on tests of frontal lobe functioning and had a greater-than-expected degree of NFT pathology in the frontal lobes, suggesting the existence of a frontal variant of AD that has distinctive clinical and pathological features.

There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This "organs-on-chips" approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs). This "tumor-on-a-chip" platform incorporates human tumor and stromal cells that grow in a 3D extracellular matrix and that depend for survival on nutrient delivery through living, perfused microvessels. Both colorectal and breast cancer cells grow vigorously in the platform and respond to standard-of-care therapies, showing reduced growth and/or regression. Vascular-targeting agents with different mechanisms of action can also be distinguished, and we find that drugs targeting only VEGFRs (Apatinib and Vandetanib) are not effective, whereas drugs that target VEGFRs, PDGFR and Tie2 (Linifanib and Cabozantinib) do regress the vasculature. Tumors in the VMT show strong metabolic heterogeneity when imaged using NADH Fluorescent Lifetime Imaging Microscopy and, compared to their surrounding stroma, many show a higher free/bound NADH ratio consistent with their known preference for aerobic glycolysis. The VMT platform provides a unique model for studying vascularized solid tumors in vitro.

A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, M pro , is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to M pro . High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science , this issue p. 642