White matter hyperintensities associate with cognitive slowing in patients with systemic lupus erythematosus and neuropsychiatric symptoms

Objective- To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes. Methods- Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42±13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally. Results- Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p≤0.05). Higher WMH volume associated with lower PS in the total group (B: −0.14 (95% CI −0.32 to −0.02)); especially in inflammatory NPSLE (B: −0.36 (95% CI −0.60 to −0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)). Conclusion- We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype

Community Justice and Public Safety: Assessing Criminal Justice Policy Through the Lens of the Social Contract

A reconceptualization of the idea of “community justice” is framed in the logic of the social contract and emphasizes the responsibility of the justice system for the provision of public safety. First, we illustrate the ways in which the criminal justice system has hindered the efforts of community residents to participate in the production of public safety by disrupting informal social networks. Then we turn to an examination of the compositional dynamics of California prison populations over time to demonstrate that the American justice system has failed to meet their obligations to provide public safety by incapacitating dangerous offenders. We argue that these policy failures represent a breach of the social contract and advocate for more effective collaboration between communities and the formal criminal justice system so that all parties can fulfill their obligations under the contract

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

The COMBREX Project: Design, Methodology, and Initial Results

© 2013 Brian P. et al.Prior to the “genomic era,” when the acquisition of DNA sequence involved significant labor and expense, the sequencing of genes was strongly linked to the experimental characterization of their products. Sequencing at that time directly resulted from the need to understand an experimentally determined phenotype or biochemical activity. Now that DNA sequencing has become orders of magnitude faster and less expensive, focus has shifted to sequencing entire genomes. Since biochemistry and genetics have not, by and large, enjoyed the same improvement of scale, public sequence repositories now predominantly contain putative protein sequences for which there is no direct experimental evidence of function. Computational approaches attempt to leverage evidence associated with the ever-smaller fraction of experimentally analyzed proteins to predict function for these putative proteins. Maximizing our understanding of function over the universe of proteins in toto requires not only robust computational methods of inference but also a judicious allocation of experimental resources, focusing on proteins whose experimental characterization will maximize the number and accuracy of follow-on predictions.COMBREX is funded by a GO grant from the National Institute of General Medical Sciences (NIGMS) (1RC2GM092602-01).Peer Reviewe

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.publishedVersionPeer reviewe

Fluorescence Detection of DNA Amplification in Porous Media for Point-of-Care Diagnostics

Thesis (Master's)--University of Washington, 2015The translation of sophisticated, laboratory-developed methods for disease diagnosis into devices appropriate for locations with limited infrastructure—whether that is a military setting, resource-poor country, or a home—requires the development of rapid, inexpensive, robust, and semi-autonomous assays. One common diagnostic testing format that addresses these requirements is the lateral flow test (LFT). These tests use modified porous substrates to automate the delivery of samples via wicking, which enables low-cost and equipment-free analysis. These tests also utilize the rehydration of reagents from dry storage in the substrate, which enables multi-step and intervention-free assays. Typically, dry reagents in LFTs are stored with sugars that preserve reagent functionality. However, the formation of concentrated sugar solutions in porous media during drying can lead to non-uniform rehydration of reagents stored by this method. Additionally, in many diagnostic assays, the uniform mixing of targets with multiple reagents at precise concentrations is critical to performance. This is especially true for LFT-based isothermal nucleic acid amplification tests (iNAATs), for which the non-uniform rehydration of reagents causes a drastic reduction in assay performance. Since iNAATs produce results more rapidly and with increased sensitivity than traditional culture-based methods, their use in the LFT format represents an ideal diagnostic test for use in low-resource settings (LRS). Therefore, further study and development of iNAAT reagent rehydration in porous media is needed to enable improved LFT-based iNAATs for disease diagnosis in LRS. To this end, we have developed a novel, quantitative, fluorescence-based method for the observation and analysis of isothermal DNA amplification from dry reagents in porous media. Here, we describe this method and accompanying analytical tools to assess variations in reagent composition, imbibition time and target input levels with direct utility for performance quantification of a real LFT-based iNAAT

Outbreaks of Disease Associated with Food Imported into the United States, 1996–2014

The proportion of US food that is imported is increasing; most seafood and half of fruits are imported. We identified a small but increasing number of foodborne disease outbreaks associated with imported foods, most commonly fish and produce. New outbreak investigation tools and federal regulatory authority are key to maintaining food safety

The COMBREX project: design, methodology, and initial results.

Experimental data exists for only a vanishingly small fraction of sequenced microbial genes. This community page discusses the progress made by the COMBREX project to address this important issue using both computational and experimental resources