Cj0596 is a periplasmic peptidyl prolyl cis-trans isomerase involved in Campylobacter jejuni motility, invasion, and colonization

Abstract Background Campylobacter jejuni is a gastrointestinal pathogen of humans, but part of the normal flora of poultry, and therefore grows well at the respective body temperatures of 37°C and 42°C. Proteomic studies on temperature regulation in C. jejuni strain 81–176 revealed the upregulation at 37°C of Cj0596, a predicted periplasmic chaperone that is similar to proteins involved in outer membrane protein folding and virulence in other bacteria. Results The cj0596 gene was highly conserved in 24 strains and species of Campylobacter, implying the importance of this gene. To study the role that Cj0596 plays in C. jejuni pathogenesis, a mutant derivative of strain 81–176 was constructed in which the cj0596 gene was precisely deleted. A revertant of this mutant was isolated by restoring the gene to its original chromosomal location using streptomycin counterselection. The cj0596 mutant strain demonstrated a slightly decreased growth rate and lower final growth yield, yet was more motile and more invasive of human intestinal epithelial cells than wild-type. In either single or mixed infections, the mutant was less able to colonize mice than 81–176. The cj0596 mutant also expressed altered levels of several proteins. Conclusion Mutation of cj0596 has an effect on phenotypes related to C. jejuni pathogenesis, probably due to its role in the proper folding of critical outer membrane proteins.</p

Valuing Information in Complex Systems: An Integrated Analytical Approach to Achieve Optimal Performance in the Beer Distribution Game

Even seemingly simple systems can produce complex dynamics, which leads management professionals to develop tools for training, monitoring, and improving performance. Management simulators provide useful insights about human behavior and interactions, while computational and informational decision support tools offer opportunities to reduce inconsistencies, errors, and non-optimal human choices, particularly for complex systems that involve multiple decision makers, uncertainty, variability, and time. We use the context of a popular management simulator that teaches students about the bullwhip effect (i.e., the beer distribution game) to explore an integrated decision analytic, control theory, and system dynamics approach to the game that recognizes the value of available (imperfect) information and considers the value of perfect information to provide the optimal strategy. Using a discrete event simulation, we characterize optimal decisions and overall team scores for the situation of actual available information and perfect information. We describe our implementation of the strategy in the field to win the 2007 beer game world championship played at the 25th conference of the International System Dynamics Society. This paper seeks to demonstrate that better understanding of the system and use of available information leads to significantly lower expected costs than identified in prior studies. Understanding complex systems and using information optimally may increase system stability and significantly improve performance, in some cases even without better information than already available

Targeting and Readout Strategies for Fast Optical Neural Control In Vitro and In Vivo

Major obstacles faced by neuroscientists in attempting to unravel the complexity of brain function include both the heterogeneity of brain tissue (with a multitude of cell types present in vivo) and the high speed of brain information processing (with behaviorally relevant millisecond-scale electrical activity patterns). To address different aspects of these technical constraints, genetically targetable neural modulation tools have been developed by a number of groups (Zemelman et al., 2002; Banghart et al., 2004; Karpova et al., 2005; Lima and Miesenbock, 2005; Thompson et al., 2005; Chambers et al., 2006; Tan et al., 2006; Gorostiza et al., 2007; Lerchner et al., 2007; Szobota et al., 2007). One approach recently brought to neurobiology, combining both high speed and genetic targeting, is based on a family of fast light-responsive microbial opsins including halorhodopsins (e.g., NpHR) and channelrhodopsins (e.g., ChR2) (for review, see Zhang et al., 2007b). These microbial opsins are single-component transmembrane conductance regulators encompassing light sensitivity and fast membrane potential control within a single open reading frame, which can be used to achieve fast bidirectional control of specific cell types even in freely moving animals (Adamantidis et al., 2007; Zhang et al., 2007a). Although the basic functioning of these tools has been reviewed previously (Zhang et al., 2007b), here we describe a collection of targeting and readout strategies designed for rapid and flexible application of the microbial opsin system, and provide pointers to the relevant literature. Combinations of these multiple levels of targeting and readout define an evolving toolbox that may open up new possibilities for basic neuroscience investigation

Optical Deconstruction of Parkinsonian Neural Circuitry

Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying mechanisms of DBS. We used optogenetics and solid-state optics to systematically drive or inhibit an array of distinct circuit elements in freely moving parkinsonian rodents and found that therapeutic effects within the subthalamic nucleus can be accounted for by direct selective stimulation of afferent axons projecting to this region. In addition to providing insight into DBS mechanisms, these results demonstrate an optical approach for dissection of disease circuitry and define the technological toolbox needed for systematic deconstruction of disease circuits by selectively controlling individual components

Developing a patient-centered outcome measure for complementary and alternative medicine therapies II: Refining content validity through cognitive interviews

BACKGROUND: Available measures of patient-reported outcomes for complementary and alternative medicine (CAM) inadequately capture the range of patient-reported treatment effects. The Self-Assessment of Change questionnaire was developed to measure multi-dimensional shifts in well-being for CAM users. With content derived from patient narratives, items were subsequently focused through interviews on a new cohort of participants. Here we present the development of the final version in which the content and format is refined through cognitive interviews. METHODS: We conducted cognitive interviews across five iterations of questionnaire refinement with a culturally diverse sample of 28 CAM users. In each iteration, participant critiques were used to revise the questionnaire, which was then re-tested in subsequent rounds of cognitive interviews. Following all five iterations, transcripts of cognitive interviews were systematically coded and analyzed to examine participants' understanding of the format and content of the final questionnaire. Based on this data, we established summary descriptions and selected exemplar quotations for each word pair on the final questionnaire. RESULTS: The final version of the Self-Assessment of Change questionnaire (SAC) includes 16 word pairs, nine of which remained unchanged from the original draft. Participants consistently said that these stable word pairs represented opposite ends of the same domain of experience and the meanings of these terms were stable across the participant pool. Five pairs underwent revision and two word pairs were added. Four word pairs were eliminated for redundancy or because participants did not agree on the meaning of the terms. Cognitive interviews indicate that participants understood the format of the questionnaire and considered each word pair to represent opposite poles of a shared domain of experience. CONCLUSIONS: We have placed lay language and direct experience at the center of questionnaire revision and refinement. In so doing, we provide an innovative model for the development of truly patient-centered outcome measures. Although this instrument was designed and tested in a CAM-specific population, it may be useful in assessing multi-dimensional shifts in well-being across a broader patient population

The potential impact of expanding target age groups for polio immunization campaigns

Background: Global efforts to eradicate wild polioviruses (WPVs) continue to face challenges due to uninterrupted endemic WPV transmission in three countries and importation-related outbreaks into previously polio-free countries. We explore the potential role of including older children and adults in supplemental immunization activities (SIAs) to more rapidly increase population immunity and prevent or stop transmission. Methods: We use a differential equation-based dynamic poliovirus transmission model to analyze the epidemiological impact and vaccine resource implications of expanding target age groups in SIAs. We explore the use of older age groups in SIAs for three situations: alternative responses to the 2010 outbreak in Tajikistan, retrospective examination of elimination in two high-risk states in northern India, and prospective and retrospective strategies to accelerate elimination in endemic northwestern Nigeria. Our model recognizes the ability of individuals with waned mucosal immunity (i.e., immunity from a historical live poliovirus infection) to become re-infected and contribute to transmission to a limited extent. Results: SIAs involving expanded age groups reduce overall caseloads, decrease transmission, and generally lead to a small reduction in the time to achieve WPV elimination. Analysis of preventive expanded age group SIAs in Tajikistan or prior to type-specific surges in incidence in high-risk areas of India and Nigeria showed the greatest potential benefits of expanded age groups. Analysis of expanded age group SIAs in outbreak situations or to accelerate the interruption of endemic transmission showed relatively less benefit, largely due to the circulation of WPV reaching individuals sooner or more effectively than the SIAs. The India and Nigeria results depend strongly on how well SIAs involving expanded age groups reach relatively isolated subpopulations that sustain clusters of susceptible children, which we assume play a key role in persistent endemic WPV transmission in these areas. Conclusions: This study suggests the need to carefully consider the epidemiological situation in the context of decisions to use expanded age group SIAs. Subpopulations of susceptible individuals may independently sustain transmission, which will reduce the overall benefits associated with using expanded age group SIAs to increase population immunity to a sufficiently high level to stop transmission and reduce the incidence of paralytic cases

Modeling undetected live poliovirus circulation after apparent interruption of transmission: implications for surveillance and vaccination

Background: Most poliovirus infections occur with no symptoms and this leads to the possibility of silent circulation, which complicates the confirmation of global goals to permanently end poliovirus transmission. Previous simple models based on hypothetical populations assumed perfect detection of symptomatic cases and suggested the need to observe no paralytic cases from wild polioviruses (WPVs) for approximately 3-4 years to achieve 95% confidence about eradication, but the complexities in real populations and the imperfect nature of surveillance require consideration. Methods: We revisit the probability of undetected poliovirus circulation using a more comprehensive model that reflects the conditions in a number of places with different characteristics related to WPV transmission, and we model the actual environmental WPV detection that occurred in Israel in 2013. We consider the analogous potential for undetected transmission of circulating vaccine-derived polioviruses. The model explicitly accounts for the impact of different vaccination activities before and after the last detected case of paralytic polio, different levels of surveillance, variability in transmissibility and neurovirulence among serotypes, and the possibility of asymptomatic participation in transmission by previously-vaccinated or infected individuals. Results: We find that prolonged circulation in the absence of cases and thus undetectable by case-based surveillance may occur if vaccination keeps population immunity close to but not over the threshold required for the interruption of transmission, as may occur in northwestern Nigeria for serotype 2 circulating vaccine-derived poliovirus in the event of insufficient tOPV use. Participation of IPV-vaccinated individuals in asymptomatic fecal-oral transmission may also contribute to extended transmission undetectable by case-based surveillance, as occurred in Israel. We also find that gaps or quality issues in surveillance could significantly reduce confidence about actual disruption. Maintaining high population immunity and high-quality surveillance for several years after the last detected polio cases will remain critical elements of the polio end game. Conclusions: Countries will need to maintain vigilance in their surveillance for polioviruses and recognize that their risks of undetected circulation may differ as a function of their efforts to manage population immunity and to identify cases or circulating live polioviruses

Assessment of the impact of the COVID-19 pandemic on health services use

OBJECTIVES: The coronavirus disease of 2019 (COVID-19) pandemic declared by the World Health Organization on March 11, 2020 impacted healthcare services with provider and patient cancellations, delays, and patient avoidance or delay of emergency department or urgent care. Limited data exist on the population proportion affected by delayed healthcare, which is important for future healthcare planning efforts. Our objective was to evaluate the impact of the COVID-19 pandemic on healthcare service cancellations or delays and delays/avoidance of emergency/urgent care overall and by population characteristics. STUDY DESIGN: This was a cross-sectional study. METHODS: Our sample (n = 2314) was assembled through a phone survey from 8/12/2020-10/27/2020 among non-institutionalized St. Louis County, Missouri, USA residents ≥18 years. We asked about provider and patient-initiated cancellations or delays of appointments and pandemic-associated delays/avoidance of emergency/urgent care overall and by participant characteristics. We calculated weighted prevalence estimates by select resident characteristics. RESULTS: Healthcare services cancellations or delays affected ∼54% (95% CI 50.6%-57.1%) of residents with dental (31.1%, 95% CI 28.1%-34.0%) and primary care (22.1%, 95% CI 19.5%-24.6%) being most common. The highest prevalences were among those who were White, ≥65 years old, female, in fair/poor health, who had health insurance, and who had ≥1 medical condition. Delayed or avoided emergency/urgent care impacted ∼23% (95% CI 19.9%-25.4%) of residents with a higher prevalence in females than males. CONCLUSIONS: Healthcare use disruptions impacted a substantial proportion of residents. Future healthcare planning efforts should consider these data to minimize potential morbidity and mortality from delayed care