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The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2-Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5' ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2-Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2-Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2-Msh3 can disrupt DNA replication and repair and highlights the role of Msh2-Msh3 protein abundance in Msh2-Msh3-mediated genomic instability., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Firefighters are routinely exposed to loud noise that put them at risk for hearing loss. A reliable and valid measure to assess firefighters' hearing function is important. This study aims to test the reliability and validity of the modified Amsterdam Inventory for Auditory Disability and Handicap ((m)AIADH) in firefighters., Method: A cross-sectional study was conducted using a convenience sample of 239 career firefighters from six partnered fire departments in Central Texas and Northern California. The internal consistency, convergent and criterion validity, and the ability to discriminate groups by measured hearing, perceived hearing, and a combination of measured and perceived hearing, were examined using the total score and score for each of the five subscales of the (m)AIADH., Results: The study participants were primarily men (93%). Satisfactory internal consistency was revealed for the (m)AIADH with Cronbach's alpha above 0.80 for all five subscales. Criterion analysis presented a moderate correlation between the (m)AIADH and the average of hearing threshold at high frequencies (4, 6, and 8 kHz). For convergent validity, the (m)AIADH was moderately to highly related with perceived hearing. There were statistically significant differences in the total (m)AIADH score and the five subscales for measured hearing thresholds except for "intelligibility in quiet." The (m)AIADH also showed a discriminative ability to distinguish between the group with good perceived hearing and the group with bad perceived hearing., Conclusion: The (m)AIADH is a reliable and valid measure to assess various dimensions of hearing function among firefighters., (© 2023 Wiley Periodicals LLC.)

Purpose: The original effort-reward imbalance (ERI) questionnaire has been widely used as a measure of occupational stress. The need for brief measurement of psychosocial stress at work has risen. This study examined the psychometric properties of a 16-item short form ERI (S-ERI) questionnaire., Methods: A cross-sectional study was conducted with a convenience sample of 247 career firefighters in the United States. An internet-based survey contained the S-ERI questionnaire, and assessed perceived health, demographics, and work characteristics. Internal consistency was tested by item-total correlation and Cronbach's α coefficients. Factorial validity was assessed by confirmatory factor analysis (CFA), and criterion validity was examined by testing the S-ERI's association with perceived health, controlling for other factors., Results: The study participants were primarily young and mid-aged White males (mean age = 42 years, 75% White non-Hispanic, 93% males). The S-ERI questionnaire showed satisfactory internal consistency, with Cronbach α coefficients above 0.80 for all three scales: effort 0.82, reward 0.83, and overcommitment 0.81. CFA showed all the S-ERI components had a good fit (goodness-of-fit index = 0.99, comparative fit index = 0.92, root mean square error of approximation = 0.06). In terms of criterion validity, significantly increased odds ratios (ORs) for perceived health (those indicating they were less healthy) were found in firefighters in the lowest tertile of reward (OR = 7.06, 95% confidence interval [CI]: 2.86-17.43), and highest tertile of overcommitment (OR = 2.29, 95% CI: 1.00-5.22), after controlling for other factors., Conclusion: The S-ERI questionnaire is a reliable and valid measure to assess occupational stress. We recommend the use of S-ERI as a measure of occupational stress when initiating efforts to improve firefighters' wellness., (© 2022 Wiley Periodicals LLC.)

Intravascular catheters are widely used among hospitals; however, their failure rates are high, up to 50%, when secured by traditional techniques, such as tape and gauze. The use of catheter securement cyanoacrylate adhesives provides a unique approach to the issues surrounding the use of traditional securement techniques for vascular access devices by providing significant securement strength, barrier properties, antibacterial properties, hemostatic properties, and flexibility. The purpose of this research was to perform a thorough and systematic review of the current literature existing regarding the use of cyanoacrylate adhesive for the care and maintenance of vascular access devices., (Copyright © 2022 Infusion Nurses Society.)

Background: With the limited availability of testing for the presence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and concerns surrounding the accuracy of existing methods, other means of identifying patients are urgently needed. Previous studies showing a correlation between certain laboratory tests and diagnosis suggest an alternative method based on an ensemble of tests., Methods: We have trained a machine learning model to analyze the correlation between SARS-CoV-2 test results and 20 routine laboratory tests collected within a 2-day period around the SARS-CoV-2 test date. We used the model to compare SARS-CoV-2 positive and negative patients., Results: In a cohort of 75 991 veteran inpatients and outpatients who tested for SARS-CoV-2 in the months of March through July 2020, 7335 of whom were positive by reverse transcription polymerase chain reaction (RT-PCR) or antigen testing, and who had at least 15 of 20 lab results within the window period, our model predicted the results of the SARS-CoV-2 test with a specificity of 86.8%, a sensitivity of 82.4%, and an overall accuracy of 86.4% (with a 95% confidence interval of [86.0%, 86.9%])., Conclusions: Although molecular-based and antibody tests remain the reference standard method for confirming a SARS-CoV-2 diagnosis, their clinical sensitivity is not well known. The model described herein may provide a complementary method of determining SARS-CoV-2 infection status, based on a fully independent set of indicators, that can help confirm results from other tests as well as identify positive cases missed by molecular testing., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objectives: Despite having close contact with the general public, members of the San Francisco Fire Department (SFFD) reported relatively few cases of COVID-19 during the first half of 2020. Our objective was to explore evidence for prior undetected infections by conducting a seroprevalence survey, and to document both risk and protective factors for prior COVID-19 infection., Methods: This cross-sectional study assessed workplace practices and exposures of SFFD personnel during the first 6 months of 2020 via questionnaire and documented prior COVID-19 infections by serologic antibody testing using an orthogonal testing protocol., Results: Of 1231 participating emergency responders, three (0.25%) had confirmed positive COVID-19 antibody results., Conclusions: Safe workplace practices, community public health intervention, and low community infection rates appear to have been protective factors for emergency responders in San Francisco during our study period., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Background: We experienced a high incidence of jejunal tube (JEJ) displacement in children who underwent percutaneous endoscopic transgastric jejunostomy (PEGJ), ever since the introduction of ENFit connector (2017)., Methods: Two interventions were introduced in 2018 - fixative suture to PEGJ ENFit connector, and conversion to balloon transgastric-jejunal feeding device (Balloon GJ) whenever possible. Children receiving PEGJ and Balloon GJ in 2.8 years were categorized into 3 eras: 2016 (pre-ENFit), 2017 (ENFit) and 2018 (interventional), for comparison of complications and sequelae. Kaplan-Meier survival curves with log-rank test (P < 0.05) were applied., Results: 100 children underwent 323 JEJ insertions - PEGJ (n = 237), Balloon GJ (n = 86). Complications occurred in 188 JEJs (58%), more frequently with PEGJ than Balloon GJ (69% vs. 29%, P < 0.0005). PEGJ had higher complication/1000-tube-days (6 vs. 0, P < 0.0005). In 2018, complication rate reduced from 76% to 30% (P < 0.0005) owing to effectiveness of PEGJ connector suture application (P = 0.019), and increased utilization of Balloon GJ (16% to 44%, P = 0.005). Balloon GJ showed better JEJ survival (P = 0.019), less morbidity (emergency attendance, X-ray) and greater cost-effectiveness than PEGJ., Conclusions: Balloon GJ had better overall outcomes than PEGJ. Suture application to connector successfully reduced JEJ internal displacement in PEGJ; however, conversion to Balloon GJ should be strongly considered., Level of Evidence: II., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a surge in clinical trials evaluating investigational and approved drugs. Retrospective analysis of drugs taken by COVID-19 inpatients provides key information on drugs associated with better or worse outcomes., Methods: We conducted a retrospective cohort study of 10 741 patients testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 3 days of admission to compare risk of 30-day all-cause mortality in patients receiving ondansetron using multivariate Cox proportional hazard models. All-cause mortality, length of hospital stay, adverse events such as ischemic cerebral infarction, and subsequent positive COVID-19 tests were measured., Results: Administration of ≥8 mg of ondansetron within 48 hours of admission was correlated with an adjusted hazard ratio for 30-day all-cause mortality of 0.55 (95% CI, 0.42-0.70; P  < .001) and 0.52 (95% CI, 0.31-0.87; P  = .012) for all and intensive care unit-admitted patients, respectively. Decreased lengths of stay (9.2 vs 11.6; P  < .001), frequencies of subsequent positive SARS-CoV-2 tests (53.6% vs 75.0%; P  = .01), and long-term risks of ischemic cerebral ischemia (3.2% vs 6.1%; P  < .001) were also noted., Conclusions: If confirmed by prospective clinical trials, our results suggest that ondansetron, a safe, widely available drug, could be used to decrease morbidity and mortality in at-risk populations., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective. To develop a valid and reliable academic resilience scale for use in the didactic portion of the Doctor of Pharmacy curriculum to identify those pharmacy students who have greater capacity to overcome academic adversity. Methods. A cross-sectional survey was conducted among first-year, second-year, and third-year pharmacy students to assess psychometric properties of a 30-item adapted academic resilience scale. Data were also collected using the Short Grit Scale (Grit-S). Demographic characteristics were collected from student records. Exploratory factor analysis was applied to determine the number of underlying factors responsible for data covariation. Principal components analysis was used as the extraction method. Varimax rotation method was used, and the Cronbach alpha was estimated. Validity testing was conducted by calculating Pearson's r correlations between the adapted academic resilience scale and Grit-S. Results. The survey response rate was 84%. The final version of the scale, the Academic Pharmacy Resilience Scale (APRS-16), had four subscales and 16 items (14 items failed to load on any of the factors and were deleted). The Cronbach alpha was .84, indicating strong internal consistency. The APRS-16 and its subscales were significantly correlated to the Grit-S and its subscales, providing evidence of effective convergent validity. Conclusion. Evidence supports the reliability and validity of the APRS-16 as a measure of academic resilience in pharmacy students. Future studies should use the APRS-16 to investigate the relationship between academic resilience and performance outcomes among pharmacy students.

Objective: The purpose of this study is to introduce a wound closure testing method that reproduces a pulling or stretching force, leading to more accurate supporting data for clinicians to select the proper product when closing a low- or high-tension incision in conjunction with deep dermal sutures., Materials and Methods: Incisions were made in the center of 70 prepared porcine skin samples. They were cleaned with isopropanol and wiped dry before applying the adhesive, as per each respective manufacturer's instructions. A tensile tester was used to pull the incisions apart and record each wound closure maximum disruption force. A paired t test assuming unequal variances was performed on the data., Results: This new wound closure test method was determined to be more advantageous when compared with previous methods in terms of approximation incision, approximation of clinical scenario, approximation directional force experienced by incision, number of steps, sample preparation time, and equipment needed. One specific 2-octyl cyanoacrylate topical skin adhesive product was revealed to have statistically significantly higher wound closure strength than most of the investigated adhesives. That topical skin adhesive exhibited a higher mean strength than all other cyanoacrylate tissue adhesives tested in this study., Conclusions: The study indicates this wound closure test has the potential to be an ideal testing method for predicting the strength of a wound-sealing adhesive subjected to a pulling or stretching force. The topical skin adhesive that demonstrated the highest mean strength of the 7 cyanoacrylate adhesive products tested potentially could be the optimal wound closure device for low- or high-tension incisions in conjunction with deep dermal sutures.

Allogrooming is a key aspect of chimpanzee sociality and many studies have investigated the role of reciprocity in a biological market. One theoretical form of reciprocity is time-matching, where payback consists of an equal duration of effort (e.g. twenty seconds of grooming repaid with twenty seconds of grooming). Here, we report a study of allogrooming in a group of twenty-six captive chimpanzees (Chester Zoo, UK), based on more than 150 hours of data. For analysis, we introduce a methodological innovation called the "Delta scale", which unidimensionally measures the accuracy of time-matching according to the extent of delay after the cessation of grooming. Delta is positive when reciprocation occurs after any non-zero delay (e.g. A grooms B and then B grooms A after a five second break) and it is negative when reciprocation begins whilst the original grooming has not yet ceased. Using a generalized linear mixed-method, we found evidence for time-matched reciprocation. However, this was true only for immediate reciprocation (Delta less than zero). If there was a temporal break in grooming between two members of a dyad, then there was no evidence that chimpanzees were using new bouts to retroactively correct for time-matching imbalances from previous bouts. Our results have implications for some of the cognitive constraints that differentiate real-life reciprocation from abstract theoretical models. Furthermore, we suggest that some apparent patterns of time-matched reciprocity may arise merely due to the law of large numbers, and we introduce a statistical test which takes this into account when aggregating grooming durations over a window of time., Competing Interests: The authors have declared that no competing interests exist.

In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11a to upregulate the expression of γ-globin (fetal hemoglobin). In these cells, disruption of the erythroid-specific enhancer of the BCL11A gene increased endogenous γ-globin expression to levels that reached or exceeded those observed following knockout of the BCL11A coding region without negatively affecting survival or in vivo long-term proliferation of edited HSPCs and other lineages. In addition, BCL11A enhancer modification in mobilized CD34+ cells from patients with β-thalassemia major resulted in a readily detectable γ-globin increase with a preferential increase in G-gamma, leading to an improved phenotype and, likely, a survival advantage for maturing erythroid cells after editing. Furthermore, we documented that both normal and β-thalassemia HSPCs not only can be efficiently expanded ex vivo after editing but can also be successfully edited post-expansion, resulting in enhanced early in vivo engraftment compared with unexpanded cells. Overall, this work highlights a novel and effective treatment strategy for correcting the β-thalassemia phenotype by genome editing.

We introduce a Schelling model in which people are modelled as agents following simple behavioural rules which dictate their tolerance to others, their corresponding preference for particular locations, and in turn their movement through a geographic or social space. Our innovation over previous work is to allow agents to adapt their tolerance to others in response to their local environment, in line with contemporary theories from social psychology. We show that adaptive tolerance leads to a polarization in tolerance levels, with distinct modes at either extreme of the distribution. Moreover, agents self-organize into communities of like-tolerance, just as they congregate with those of same colour. Our results are robust not only to variations in free parameters, but also experimental treatments in which migrants are dynamically introduced into the native population. We argue that this model provides one possible parsimonious explanation of the political landscape circa 2016.

Poor insight in schizophrenia is prevalent across cultures and phases of illness. In this review, we examine the recent research on the relationship of insight with behavior, mood and perceived quality of life, on its complex roots, and on the effects of existing and emerging treatments. This research indicates that poor insight predicts poorer treatment adherence and therapeutic alliance, higher symptom severity and more impaired community function, while good insight predicts a higher frequency of depression and demoralization, especially when coupled with stigma and social disadvantage. This research also suggests that poor insight may arise in response to biological, experiential, neuropsychological, social-cognitive, metacognitive and socio-political factors. Studies of the effects of existing and developing treatments indicate that they may influence insight. In the context of earlier research and historical models, these findings support an integrative model of poor insight. This model suggests that insight requires the integration of information about changes in internal states, external circumstances, others' perspectives and life trajectory as well as the multifaceted consequences and causes of each of those changes. One implication is that treatments should, beyond providing education, seek to assist persons with schizophrenia to integrate the broad range of complex and potentially deeply painful experiences which are associated with mental illness into their own personally meaningful, coherent and adaptive picture., (© 2018 World Psychiatric Association.)

Transplantation of small cord blood (CB) units, or of autologous ex vivo-genetically modified adult hematopoietic stem cells (HSC), face the common challenge of suboptimal HSC doses for infusion and impaired engraftment of the transplanted cells. Ex vivo expansion of HSCs, using either cell-based coculture approaches or especially small molecules have been successfully tested mainly in CB and in prolonged cultures. Here, we explored whether innovative combinations of small molecules can sufficiently, after short culture, expand adult HSCs while retaining their functionality in vivo. We found that 5-day cultured cells, in the presence of the small molecule combinations tested, achieved higher engraftment levels in NSG mice than both their uncultured and their cytokine only-cultured counterparts. Surprisingly, the engraftment levels were neither concordant to the numbers of phenotypically similar HSCs expanded under different small molecule combinations, nor explained by their distinct companion cells present. Transcriptomic comparative analysis of sorted, phenotypically similar, ex vivo generated HSCs transplanted in equal numbers, suggested that HSCs generated under expansion conditions that maintain low expression of the Rap1/Ras/PI3K-AKT pathway exhibit a superior functional profile in vivo. Stem Cells Translational Medicine 2017;6:1852-1858., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

The Austrian psychiatrist Theodor Meynert's anatomical theories of the brain and nerves are laden with metaphorical imagery, ranging from the colonies of empire to the tentacles of jellyfish. This paper analyses among Meynert's earliest works a different set of less obvious metaphors, namely, the fibres, threads, branches and paths used to elaborate the brain's interior. I argue that these metaphors of material, or what the philosopher Gaston Bachelard called 'material images', helped Meynert not only to imaginatively extend the tracts of fibrous tissue inside the brain but to insinuate their function as pathways co-extensive with the mind. Above all, with reference to Bachelard's study of the material imagination, I argue that Meynert helped entrench the historical intuition that the mind, whatever it was, consisted of some interiority - one which came to be increasingly articulated through the fibrous confines of the brain.

The purpose of this study was to determine the prevalence and characteristics of tinnitus and assess the relationship between tinnitus and hearing loss among firefighters and operating engineers, who are exposed to noise on-the-job. The study analyzed existing data from two different populations (154 firefighters and 769 operating engineers) who completed a survey and audiometric tests as part of a hearing loss prevention intervention study. Approximately 40% of both groups reported tinnitus; 34% of firefighters and 59% of operating engineers showed hearing loss at noise-sensitive frequencies (4 kHz and 6 kHz). Firefighters with high frequency hearing loss (odds ratio [OR] = 2.31; 95% confidence interval [CI] = [1.05, 5.11]) and those with perceived impaired hearing status (OR = 3.53; 95% CI = [1.27, 9.80]) were significantly more likely to report tinnitus. Similarly, operating engineers who had hearing loss at both low (OR = 2.10; 95% CI = [1.40, 3.15]) and high frequencies (OR = 2.00; 95% CI = [1.37, 2.90]), and perceived impaired hearing status (OR = 2.17; 95% CI = [1.55, 3.05]) were twice as likely to report tinnitus. This study demonstrated that tinnitus is a considerable problem for noise-exposed workers. Workers with hearing loss demonstrated significantly higher rates of tinnitus. Comprehensive workplace hearing conservation programs should include tinnitus management for noise-exposed workers, along with other key elements such as noise control and hearing protection., (© 2016 The Author(s).)

Organisms can adapt to variable environments by using environmental cues to modulate developmental gene expression. In principle, maternal influences can adaptively adjust offspring phenotype when early life and adult environments match, but they may be maladaptive when future environments are not predictable. One of the best-studied 'maternal effects' is through modification of the offspring's hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine system that controls responses to stress. In addition to the direct transfer of glucocorticoids from mother to offspring, offspring HPA function and other phenotypes can also be affected by epigenetic modifications like DNA methylation of the glucocorticoid receptor promoter. Here we examine how among-year variation in rainfall is related to DNA methylation during development and fitness in adulthood in the superb starling (Lamprotornis superbus), which lives in a climatically unpredictable environment where early life and adult environments are unlikely to match. We found that DNA methylation in the putative promoter of the glucocorticoid receptor gene is reduced in chicks - particularly in males - born following drier prebreeding periods. Additionally, DNA methylation is lower in males that become breeders than those that never breed. However, there is no relationship in females between DNA methylation and the likelihood of dispersing from the natal group to breed elsewhere. These results suggest that early life conditions may positively affect fitness in a sex-specific manner through chemical modification of an HPA-associated gene. This study is the first to show that epigenetic modifications during early life may influence the fitness of free-living organisms adapted to unpredictable environments., (© 2015 John Wiley & Sons Ltd.)

Spurned by the increasing concern and consciousness of traumatic brain injuries in deployed U.S. service members, the U.S. Army Rapid Equipping Force sought help from the Georgia Tech Research Institute to rapidly develop and deploy a system capable of gathering relevant soldier-centric data-the Integrated Blast Effects Sensor Suite. To meet aggressive program milestones and requirements, Georgia Tech Research Institute engaged in rapid systems engineering efforts focused on leveraging iterative development and test methodologies. Ultimately, an integrated system of systems composed of vehicle systems, soldier-worn headset and torso systems, and data retrieval systems was deployed to troops in Afghanistan for an operational assessment. The Integrated Blast Effects Sensor Suite development process and parallel efforts investigating injury dosimetry methodologies have yielded unique findings and lessons learned, which should be incorporated into future evolutions of similar systems., (Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.)

In recent U.S. military experience, widespread exposure to improvised explosive devices has been implicated in noticeable changes in the incidence of brain injuries inversely related to reduced mortality--thought to be the unintended consequence of increase in exposure to blast wave effects--secondary to improved vital organ protection, improved personal protective equipment. Subsequently, there is a growing need for the development and fielding of fully integrated sensor systems capable of both capturing dynamic effects (i.e., "blast") on the battlefield--providing critical information for researchers, while providing value to the medical community and leaders--for development of pre-emptive measures and policies. Obtaining accurate and useful data remains a significant challenge with a need for sensors which feed systems that provide accurate interpretation of dynamic events and lend to an enhanced understanding of their significance to the individual. This article describes lessons learned from a data analysis perspective of a collaborative effort led by a team formed at Georgia Tech Research Institute to develop a "sensor agnostic" system that demonstrates full integration across variant platforms/systems. The system is designed to allow digital and analog time/frequency data synchronization and analysis, which facilitated the development of complex multimodal modeling/algorithms., (Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.)

Objective: To examine relationships among students' Pre-NAPLEX scores and prepharmacy, pharmacy school, and demographic variables to better understand factors that may contribute to Pre-NAPLEX performance., Methods: A retrospective review of pharmacy students' Pre-NAPLEX scores, demographics, prepharmacy factors, and pharmacy school factors was performed. Bivariate (eg, ANOVA) and correlational analyses and stepwise linear regression were conducted to examine the significance of various factors and their relationship to Pre-NAPLEX score., Results: 168 students were included, with the majority being female (60.7%) and White (72%). Mean Pre-NAPLEX score was 68.95 ± 14.5. Non-Hispanic White students had significantly higher Pre-NAPLEX scores compared to minority students (p<0.001). Pre-NAPLEX score was correlated (p<0.001) to race/ethnicity (r=-0.341), PCAT score (r=0.272), and pharmacy school GPA (r=0.346). The regression model (adjusted R(2)=0.216; p<0.001) included pharmacy school GPA, academic probation, academic remediation, and PCAT composite., Conclusion: This study highlighted that select demographic, prepharmacy, and pharmacy school factors were associated with Pre-NAPLEX outcomes. Such factors may assist colleges/schools of pharmacy in identifying students who may be at risk for poorer NAPLEX performance and may need greater preparation.

The objective of this study was to investigate new methods for predicting injury from expected spaceflight dynamic loads by leveraging a broader range of available information in injury biomechanics. Although all spacecraft designs were considered, the primary focus was the National Aeronautics and Space Administration Orion capsule, as the authors have the most knowledge and experience related to this design. The team defined a list of critical injuries and selected the THOR anthropomorphic test device as the basis for new standards and requirements. In addition, the team down-selected the list of available injury metrics to the following: head injury criteria 15, kinematic brain rotational injury criteria, neck axial tension and compression force, maximum chest deflection, lateral shoulder force and displacement, acetabular lateral force, thoracic spine axial compression force, ankle moments, and average distal forearm speed limits. The team felt that these metrics capture all of the injuries that might be expected by a seated crewmember during vehicle aborts and landings. Using previously determined injury risk levels for nominal and off-nominal landings, appropriate injury assessment reference values (IARVs) were defined for each metric. Musculoskeletal deconditioning due to exposure to reduced gravity over time can affect injury risk during landing; therefore a deconditioning factor was applied to all IARVs. Although there are appropriate injury data for each anatomical region of interest, additional research is needed for several metrics to improve the confidence score.

Objective: Test a radically simple school-based point-of-dispensing model., Design: Prospective study., Setting: Community, Participants: Community residents with children at one middle school., Interventions: Rapid dispensing of medication., Main Outcome Measure(s): 1) Measure and extrapolate ability to distribute medications to Darien residents through school-based distribution model; 2) assess if using a limited staffing model with limited training was functional. Identify stress points; 3) understand the existing school communication model; 4) track and extrapolate the breakdown of adult-to-child doses distributed and compare to existing census data; and 5) measure throughput of school-based distribution model in the 50-minute drop-off period., Results: 1) This exercise supported the concept that rapid medication distribution through the public schools is an appropriate strategy for health departments, particularly departments with limited resources. 2) Just-in-time briefing worked well as a training strategy. The primary stress points identified were in restock-if medication was in blister packs, we would not be able to stock vests with 100 of each as they are substantially bigger than mints. 3) The secure Darien Public School notification system was ideal for distributing information to parents since they tend to receive school communication on a regular basis and by definition, access is limited to town residents. 4) When asked about household size, most drivers indicated "two adults and two (or more) children." We distributed medication for 784 adults and 963 children. This ratio was higher than the 2010 Census, which had an average household size of 3.08 in Darien. 5) In 50 minutes, using a mix of Health Department and school staff, medication was distributed to 1,747 residents, almost 10 percent of the population. The hourly throughput from this model was distribution to 2,096 people per hour or 699 people per distributor per hour. This compares favorably to almost every other nonmedical distribution model., Conclusions: Using four Health Department staff and six public school staff, we distributed medication to 784 adults and 963 pediatric residents in 50 minutes at one school. If we extrapolated that across the six other public schools in Darien, we could provide medication to more than 10,000 residents within 8 hours. While we are cognizant of the limitations and drawbacks of this model, we strongly believe that it is the only practical solution to the problem of rapid distribution of medication to the entire community.

In 2012, the American Association of Occupational Health Nurses, Inc. (AAOHN) conducted an online membership survey. This article presents demographic, certification, educational, employment, priority issues, and membership data for advanced practice registered nurse (APRN) AAOHN members. Approximately 8% of the respondents identified themselves as nurse practitioners and/or clinical nurse specialists. The majority of these members are currently employed as APRNs (62.1%) and work full-time (85.7%) as employees of their organizations (85.8%). Critical issues that AAOHN APRN members identified in occupational health nursing practice today included the economy, government regulations, and health care reform., (Copyright 2013, SLACK Incorporated.)

The aim of this study was to assess the type of occupational injuries, duty status, and factors associated with injuries among firefighters. A total of 437 firefighters from three U.S. states participated in an Internet-based survey. Approximately 66% of firefighters experienced occupational injuries and 56% reported multiple injuries. The most commonly reported injuries were muscle strains and sprains (74%), extremity injuries (60%), back injuries (54%), and burns (28%). A significant number of firefighters reported no duty (58%) or modified duty (46%). Firefighters with more than 17 years in fire services were more likely to report injuries (odds ratio [OR] = 2.96; 95% confidence interval [CI] = 1.92-4.58) and multiple injuries (OR = 2.47; 95% CI = 1.49-4.10). Hispanics (OR = 0.34; 95% CI = 0.15-0.76) and those with stronger organizational commitments (OR = 0.54; 95% CI = 0.35-0.84) were less likely to report injuries. Several factors were associated with injuries. These factors should be incorporated into interventions to reduce occupational injuries., (Copyright 2012, SLACK Incorporated.)

Diamond-Blackfan anemia is a congenital hypoproliferative macrocytic anemia and 5q- syndrome myelodysplastic syndrome is an acquired hypoproliferative macrocytic anemia. Their common erythroid phenotype reflects a shared pathophysiology-haploinsufficiency of one of many ribosomal proteins and somatic deletion of one allele of the ribosomal protein S14 gene, respectively. Although these abnormalities lead to defective ribosome biogenesis, why ribosomal protein hemizygosity results in anemia is not certain. Here, we characterize the hematopoietic phenotype of mice lacking one allele of the ribosomal protein S6 gene. The mice have an erythroid phenotype similar to both Diamond-Blackfan anemia and the 5q- syndrome and lenalidomide therapy improves their anemia., (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Purpose: We report our experience of managing eight babies who presented with neonatal intestinal obstruction and whose rectal biopsies showed severely immature ganglion cells., Methods: Neonatal unit records were reviewed to detect patients with suspected Hirschsprung's disease or functional intestinal obstruction. Those with intestinal atresia, anorectal malformation, malrotation, cystic fibrosis and prematurity were excluded., Results: We identified 73 patients born at term. Twenty-seven did not need a rectal biopsy. Twenty-one had biopsy proven Hirschsprung's disease, while 17 had a normal rectal biopsy. Eight patients, all of whom presented with severe abdominal distension, showed immature ganglion cells. Seven had failed to pass meconium after birth. X-rays in all patients showed distended loops of bowel. Two neonates underwent an emergency laparotomy and a stoma. A repeat biopsy at 3 months showed maturation of ganglion cells and the stoma was reversed. Rectal biopsy was repeated in two other patients 2-9 months after the first biopsy and showed mature ganglion cells. At follow-up, one patient still suffers from severe constipation. Seven are asymptomatic now, including the two patients who needed a stoma., Conclusion: Immature ganglion cells on rectal biopsy may be an indicator of transient functional immaturity of the intestine.

We introduce a method for strategy acquisition in nonzero-sum n -player games and empirically validate it by applying it to a well-known benchmark problem in this domain, namely, the double-auction market. Many existing approaches to strategy acquisition focus on attempting to find strategies that are robust in the sense that they are good all-round performers against all-comers. We argue that, in many economic and multiagent scenarios, the robustness criterion is inappropriate; in contrast, our method focuses on searching for strategies that are likely to be adopted by participating agents, which is formalized as the size of a strategy's basins of attraction under the replicator dynamics.

Alterations in genes encoding transforming growth factor-beta-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-beta signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2(-/-) mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected Smad3(-/-) or Rag2(-/-) mice alone. Adoptive transfer of WT CD4(+)CD25(+) T-regulatory cells provided significant protection of Smad3/Rag2-DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3(-/-) T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2-DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-kappaB activation, increased Bcl(XL)/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-gamma, IL-1alpha, TNF-alpha, IL-1beta, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-kappaB activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues.

Objective: Describe a multilevel model of decontamination capacity for hospitals., Design: Descriptive model., Setting: Acute care hospitals with decontamination responsibilities., Patients, Participants: None., Interventions: None., Main Outcome Measure(s): None., Results: This multilevel model of defining decontamination capacity would allow more realistic assessment of current capacity, allow for fluctuating service levels depending on time of day, incorporate realistic ramp-up and ramp-down of decontamination services, allow for a defined fall-back decontamination model should decontamination processes fail, allow hospitals to define long-term decontamination service level goals, and allow better understanding of when and why to focus on low-risk/low-resource patients rather than high-risk/high-resource patients., Conclusions: This multiple-level model would allow for more realistic and effective hospital-based decontamination service models and should become part of the national decontamination paradigm.

Synovial sarcoma most commonly affects adults in the third to fifth decades of life, and is the most common sarcoma of the foot. The tumors are encapsulated and frequently in contact with bone. Because there are often few anatomical barriers, malignant spread to surrounding nerves and vasculature is common. This article discusses the case of a young patient who presented to the foot and ankle clinic with soft tissue swelling in the right foot, and the imaging protocol for such a patient. A literature review of synovial sarcoma is also presented.

Introduction: Only 4% of the United States Homeland Security funding for public safety terrorism preparedness is allotted to emergency medical services (EMS), despite the primary threat from a mass-terrorism chemical weapons attack (MTCWA) being personal injury. This study examines the preparedness of the EMS to respond to, treat, and transport victims of such attacks., Hypothesis: It was hypothesized that US EMS agencies lack the necessary equipment to mitigate large-scale morbidity and mortality from a MTCWA., Methods: Seventy after-action reports from full-scale, chemical weapons exercises conducted in large cities across the US were examined by the Office of Domestic Preparedness, Chemical Weapons Improved Response Program to ascertain if EMS responders had personal protective equipment sufficient to operate at the scene of a MTCWA., Results: Of the 50 after action reports that mentioned EMS personal protective equipment, only six (12%) EMS agencies equipped their staff with personal protective equipment., Conclusions: Results indicate that EMS responders are not prepared to safely respond to MTCWAs, which may result in a significant loss of life of victims and responders.

Hospitals, even five years past the events of September 11, with their unguarded front doors and unlocked patient rooms have conspicuously failed to implement even basic security procedures to protect the society's most vulnerable against violence. The degree of complacency is so great that even hospitals that have experienced shootings refuse to institute basic security measures such as metal detectors and identification checks. Over the six-month period, from June through December 2006, there were at least eight hospital shootings in the United States and Canada. This article outlines these shootings and presents a model "Code Silver" policy that hospitals can adopt to mitigate some of the risk of internal hospital shootings. Key concepts of the policy include training hospital staff to "shelter in place" during a violent event, marking locked doors, and having hospital security respond in an appropriate manner.

We examined the public health effects of the Northeast blackout of August 2003 and the emergency response to the blackout by the New York City Department of Health and Mental Hygiene (DOHMH). We reviewed departmental documents from the DOHMH Emergency Operations Center and surveyed DOHMH employees to identify deficiencies in the response and elicit suggestions for improvement. DOHMH deployed its all-hazards, scalable public health Incident Management System to respond to several impacts: (1) failure of multiple hospital emergency generators; (2) patients dependent on electrically powered equipment; (3) loss of electronic data input to the DOHMH syndromic surveillance system from hospital emergency departments; (4) potential for vaccine spoilage due to loss of refrigeration; (5) beach contamination with untreated sewage; (6) heat-related health effects and increase of foodborne disease; and (7) potential for an increased rodent population as a result of increased amounts of discarded perishables. Areas identified for improvement included communications during the event, DOHMH dependence on an external source of electricity, facility management during the response, and lack of readily available and appropriate emergency supplies.

Background: The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC(4) synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A(-444)C) in the gene might be associated with asthma severity and aspirin intolerance., Objective: We sought to screen the LTC(4) synthase gene for polymorphisms and to determine whether there is an association between these polymorphisms and asthma severity or aspirin sensitivity in a large, well-phenotyped population and to determine whether this polymorphism is functionally relevant., Methods: The coding regions of the LTC(4) synthase gene were screened for polymorphisms and the A(-444)C polymorphism was analyzed in a large Australian white adult population of mild (n=282), moderate (n=236), and severe asthmatic subjects (n=86) and nonasthmatic subjects (n=458), as well as in aspirin-intolerant asthmatic subjects (n=67). The functional activity of the promoter polymorphism was investigated by transient transfection of HL-60 cells with a promoter construct., Results: A new polymorphism was identified in intron 1 of the gene (IVS1-10c>a) but was not associated with asthma. Association studies showed that the A(-444)C polymorphism was weakly associated with asthma per se, but there was no association between the C(-444) allele and chronic asthma severity or aspirin intolerance. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity in C(-444) allele frequencies within different clinical subgroups. In vitro functional studies showed no significant differences in transcription efficiency between constructs containing the A(-444) allele or the C(-444) allele., Conclusions: Our data confirm that, independent of transcriptional activity, the C(-444) allele in the LTC(4) synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance.

Background: Airway inflammation in asthma is associated with cysteinyl leukotriene and prostaglandin D(2) production. Measurement of urinary metabolites of these eicosanoids may be useful for monitoring asthma patients. However, the influence of asthma phenotype and severity on basal urinary excretion of these metabolites is unknown., Objective: To compare urinary leukotriene (LT)E(4) and 9 alpha, 11 beta-prostaglandin (PG)F(2) concentrations in large groups of mild, moderate and severe asthmatic patients and healthy control subjects., Methods: Asthma severity, treatment and aspirin sensitivity were assessed by questionnaire in 168 asthmatic patients. Basal LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations were measured in urine samples from these patients and from 175 control subjects using enzyme immunoassays., Results: Urinary LTE(4) was correlated with 9 alpha, 11 beta-PGF(2) in both control subjects and asthmatic patients (P<0.002). Median LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations in patients with severe asthma were significantly reduced compared with mild asthmatic patients (P<0.05 and <0.001, respectively). Urinary 9 alpha, 11 beta-PGF(2), but not LTE(4) was lower in asthmatic patients using inhaled corticosteroids (P<0.02). Multiple regression analysis indicated that urinary 9 alpha, 11 beta-PGF(2) concentration was negatively correlated with asthma severity (P=0.003) and also with % predicted FEV(1) (forced expiratory volume in 1 s) (P=0.005)., Conclusions: Baseline urinary LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations are of limited value in discriminating between patients with different severities of asthma. Reduced urinary LTE(4) and 9 alpha, 11 beta-PGF(2) in patients with severe asthma suggest that direct or indirect effects of high-dose corticosteroid therapy combined with other factors associated with severe asthma may influence eicosanoid production. However, the negative association of urinary 9 alpha, 11 beta-PGF(2) with lung function suggests an adverse effect of chronic PGD(2) production on lung function in asthma, irrespective of severity.

Objective: To describe a previously unreported complication (severe perineal pain) after bladder reconstruction and enterocystoplasty in patients with bladder exstrophy., Patients and Methods: The notes were reviewed retrospectively for four patients (two boys and two girls) with classical bladder exstrophy who had severe penile or perineal pain after bladder reconstruction. They were all continent and using intermittent catheterization. A range of conservative management failed and all patients subsequently required excision of their native bladders between 1997 and 2000., Results: All four patients had perineal or penile pain which began 4 months to 8 years after bladder augmentation. Investigations included plain abdominal X-ray, renal and bladder ultrasonography, computerized tomography of the pelvis, video-urodynamics and cysto-urethroscopy. When therapeutic interventions such as more frequent bladder washouts, analgesic and anticholinergic drugs, and cystolithotomy (two patients) were unsuccessful in alleviating the symptoms, all had their native bladder excised. Histological examination of the excised tissue showed neither normal urothelium nor enteric mucosa at the margins of the excision; two patients already had squamous metaplasia within what represented the bladder, and in the others squamous epithelium was present amongst the enteric mucosa. All four children were pain-free with a follow-up of 2-6 years., Conclusion: All four patients developed severe referred bladder pain that was probably secondary to the abnormal retained bladder remnants. Cystectomy cured the pain and may also have removed a potential site of future malignant tumour.

Objective: To describe clinical characteristics associated with analgesia utilization in the intensive care unit., Design: A prospective cohort study of adult patients admitted to a medical intensive care unit., Subjects: Four hundred adult patients., Setting: Twelve-bed medical intensive care unit of an inner-city, university-affiliated hospital., Measurements and Main Results: Collected data included demographics, sedation and neuromuscular blocking agents used, mechanical ventilation, hemodynamic monitoring, Therapeutic Intervention Scoring System score, Logistic Organ Dysfunction System (LODS) score, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Hospital outcome was noted. The odds ratio and 95% confidence intervals were determined by using multiple logistic regression analyses. Patients' mean age (+/-sd) was 47.8 +/- 17.1 yrs; 58% were male, 84% African-American. Their APACHE II-predicted hospital mortality rate was 33%. Analgesics were used in 36% of patients. There were no differences in demographics, initial LODS score, APACHE II score, and mechanical ventilation use between patients who did and did not receive analgesics. Multiple logistic regression analysis showed that analgesic use was independently associated with sedation (odds ratio, 2.47; 95% confidence interval, 1.47-4.14), neuromuscular blockade (odds ratio, 4.98; 95% confidence interval, 1.85-13.41), and pulmonary artery flotation catheter utilization (odds ratio, 2.31; 95% confidence interval, 1.27-4.20). The median duration of mechanical ventilation was 5 days for those who received analgesia compared with 2 for those who did not (p =.0001). The median length of stay in the intensive care unit (4 vs. 2, p <.0001) and hospital (11 vs. 7, p <.0001) was higher in patients who received analgesics. There were no significant differences in intensive care unit and hospital mortality rates between patients who did and did not receive analgesics., Conclusions: Intensive care unit patients for whom analgesics were prescribed have a higher frequency of hemodynamic monitoring and use of sedative and neuromuscular blocking agents, more mechanical ventilation days, and longer intensive care unit and hospital lengths of stay.

Although there is a growing interest in understanding how perceptual mechanisms influence behavioral evolution, few studies have addressed how perception itself is shaped by evolutionary forces. We used a combination of artificial neural network models and behavioral experiments to investigate how evolutionary history influenced the perceptual processes used in mate choice by female túngara frogs. We manipulated the evolutionary history of artificial neural network models and observed an emergent bias toward calls resembling known ancestral states. We then probed female túngara frogs for similar preferences, finding strong biases toward stimuli that resemble a call hypothesized for a recent ancestor. The data strongly suggest that female túngara frogs exhibit vestigial preferences for ancestral calls, and provide a general strategy for exploring the role of historical contingency in perceptual biases.

Duchenne muscular dystrophy (DMD) is an inherited, severe muscle wasting disease caused by the loss of the cytoskeletal protein, dystrophin. Patients usually die in their late teens or early twenties of cardiac or respiratory failure. We have previously demonstrated that the dystrophin related protein, utrophin is able to compensate for the loss of dystrophin in the mdx mouse, the mouse model of the disease. Expression of a utrophin transgene under the control of an HSA promoter results in localization of utrophin to the sarcolemma and prevents the muscle pathology. Here we show that the over-expression of full-length utrophin in a broad range of tissues is not detrimental in the mdx mouse. These findings have important implications for the feasibility of the up-regulation of utrophin in therapy for DMD since they suggest that tissue specific up-regulation may not be necessary.

Evolutionary psychologists have emphasized the importance of natural selection in shaping cognitive functions, but historical contingency has not received direct study. This is crucial because in response to selection, complex traits tend to be fine-tuned or jury-rigged rather than totally reconstructed. We hypothesize that the neural and cognitive strategies an animal employs in signal recognition are influenced by the strategies used by its ancestors. The responses of female túngara frogs to ancestral calls and to calls of other closely related species are influenced by history. By training artificial neural networks with a series of calls that mimic the species' past history of call evolution or various control histories, we have shown that only networks that evolved through the mimetic history predict the response biases of túngara frogs.

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

The purpose of this study was to determine if phenytoin protein binding and metabolism were altered in prepubescent pediatric patients within the first 10 days following severe, acute traumatic brain injury. Patients (n = 10) received phenytoin loading doses (15-20 mg/kg) followed by a maintenance regimen (7 mg/kg/day) initiated within 12 hours of the loading dose. Phenytoin serum concentrations were measured serially on days 1, 2, 3, 5, 7, 9, and 10 at 1, 6, and 12 hours. Time-invariant and time-variant Michaelis-Menten pharmacokinetic models were fit to the unbound phenytoin concentration-time data (ADAPT II). Albumin concentrations significantly decreased over time (p < 0.001) and were predictive of the phenytoin binding ratio (r2 = 0.373, p < 0.0001). The time-variant model provided a superior fit of the data in 7 patients with no difference between models in 3 patients. Rapid inhibition of metabolism (Vmaxbaseline = 2.82 +/- 2.35 mg/kg/day) was observed initially following injury. This was followed by induction of metabolism as reflected by a Vmaxinduced of 20.79 +/- 13.71 mg/kg/day, which was approximately twofold higher than reported values for nonstressed children. Children with severe, acute neurotrauma were found to have markedly altered protein binding and phenytoin metabolism.