Cumulative Blast Impulse Is Predictive for Changes in Chronic Neurobehavioral Symptoms Following Low Level Blast Exposure during Military Training.

INTRODUCTION: Cumulative low-level blast exposure during military training may be a significant occupational hazard, increasing the risk of poor long-term outcomes in brain function. US Public Law 116-92 section 717 mandates that US Department of Defense agencies document the blast exposure of each Service member to help inform later disability and health care decisions. However, which empirical measures of training blast exposure, such as the number of incidents, peak overpressure, or impulse, best inform changes in the neurobehavioral symptoms reflecting brain health have not been established. MATERIALS AND METHODS: This study was approved by the US Army Special Operations Command, the University of North Carolina at Chapel Hill, and the VA Puget Sound Health Care System. Using methods easily deployable across different organizational structures, this study sought to identify and measure candidate risk factors related to career occupational blast exposure predictive of changes in neurobehavioral symptom burden. Blast dosimetry-symptom relationships were first evaluated in mice and then tested in a military training environment. In mice, the righting time neurobehavioral response was measured after exposure to a repetitive low-level blast paradigm modeled after Special Operations training. In the military training environment, 23 trainees enrolled in a 6-week explosive breaching training course, 13 instructors, and 10 Service member controls without blast exposure participated in the study (46 total). All participants provided weekly Neurobehavioral Symptom Inventory (NSI) surveys. Peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service were analyzed by Bayesian analysis of regression modeling to determine their probability of influence on the post-training symptoms reported by participants. RESULTS: We tested the hypothesis that cumulative measures of low-level blast exposure were predictive of changes in neurobehavioral symptoms. In mice, repetitive blast resulted in reduced righting times correlated with cumulative blast impulse. In Service members, peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service all showed strong evidence of influence on NSI scores after blast exposure. However, only models including baseline NSI scores and cumulative blast impulse provided significant predictive value following validation. CONCLUSIONS: These results indicate that measures of cumulative blast impulse may have utility in predicting changes in NSI scores. Such paired dosimetry-symptom measures are expected to be an important tool in safely guiding Service members' occupational exposure and optimizing force readiness and lethality.

Monitoring of Visible Particles in Parenteral Products by Manual Visual Inspection-Reassessing Size Threshold and Other Particle Characteristics that Define Particle Visibility.

Visible particles are a critical quality attribute for parenteral products and must be monitored. A carefully designed, executed, and controlled drug product manufacturing process including a final 100 % visual inspection and appropriate end-product controls ensures that visible particles are consistently minimized and demonstrates that the injectable DP is practically free from visible particles. Visual inspection, albeit appearing as a simple analytical procedure, requires several technical and operational controls to ensure adequate performance. To gather new data on particle visibility and shed light on this decade-old challenge, a multi-company blinded visual inspection threshold study was conducted. A major goal of the study was visual assessment of several particle types of different sizes in small volume vials, as a challenging configuration for visual inspection, across 9 biopharmaceutical companies in order to determine the visibility limit. The study results provide key insights into limitations and challenges of visual inspection, namely, no universal visibility limit can be applied to all particle types as the detectability varies with particle type, number, and size. The study findings underscore the necessity of setting realistic expectations on size-based visibility limits in visual inspection, robust procedures for analyst training and qualification, and harmonization of guidelines globally.

Persistent neuronal activity in human prefrontal cortex links perception and action.

How do humans flexibly respond to changing environmental demands on a sub-second temporal scale? Extensive research has highlighted the key role of the prefrontal cortex in flexible decision-making and adaptive behavior, yet the core mechanisms that translate sensory information into behavior remain undefined. Utilizing direct human cortical recordings, we investigated the temporal and spatial evolution of neuronal activity, indexed by the broadband gamma signal, while sixteen participants performed a broad range of self-paced cognitive tasks. Here we describe a robust domain- and modality-independent pattern of persistent stimulus-to-response neural activation that encodes stimulus features and predicts motor output on a trial-by-trial basis with near-perfect accuracy. Observed across a distributed network of brain areas, this persistent neural activation is centered in the prefrontal cortex and is required for successful response implementation, providing a functional substrate for domain-general transformation of perception into action, critical for flexible behavior.

Age-Related Changes in 1/f Neural Electrophysiological Noise.

Aging is associated with performance decrements across multiple cognitive domains. The neural noise hypothesis, a dominant view of the basis of this decline, posits that aging is accompanied by an increase in spontaneous, noisy baseline neural activity. Here we analyze data from two different groups of human subjects: intracranial electrocorticography from 15 participants over a 38 year age range (15-53 years) and scalp EEG data from healthy younger (20-30 years) and older (60-70 years) adults to test the neural noise hypothesis from a 1/f noise perspective. Many natural phenomena, including electrophysiology, are characterized by 1/f noise. The defining characteristic of 1/f is that the power of the signal frequency content decreases rapidly as a function of the frequency (f) itself. The slope of this decay, the noise exponent (χ), is often <-1 for electrophysiological data and has been shown to approach white noise (defined as χ = 0) with increasing task difficulty. We observed, in both electrophysiological datasets, that aging is associated with a flatter (more noisy) 1/f power spectral density, even at rest, and that visual cortical 1/f noise statistically mediates age-related impairments in visual working memory. These results provide electrophysiological support for the neural noise hypothesis of aging. Significance statement: Understanding the neurobiological origins of age-related cognitive decline is of critical scientific, medical, and public health importance, especially considering the rapid aging of the world's population. We find, in two separate human studies, that 1/f electrophysiological noise increases with aging. In addition, we observe that this age-related 1/f noise statistically mediates age-related working memory decline. These results significantly add to this understanding and contextualize a long-standing problem in cognition by encapsulating age-related cognitive decline within a neurocomputational model of 1/f noise-induced deficits in neural communication.

On the necessity of U-shaped learning.

A U-shaped curve in a cognitive-developmental trajectory refers to a three-step process: good performance followed by bad performance followed by good performance once again. U-shaped curves have been observed in a wide variety of cognitive-developmental and learning contexts. U-shaped learning seems to contradict the idea that learning is a monotonic, cumulative process and thus constitutes a challenge for competing theories of cognitive development and learning. U-shaped behavior in language learning (in particular in learning English past tense) has become a central topic in the Cognitive Science debate about learning models. Antagonist models (e.g., connectionism versus nativism) are often judged on their ability of modeling or accounting for U-shaped behavior. The prior literature is mostly occupied with explaining how U-shaped behavior occurs. Instead, we are interested in the necessity of this kind of apparently inefficient strategy. We present and discuss a body of results in the abstract mathematical setting of (extensions of) Gold-style computational learning theory addressing a mathematically precise version of the following question: Are there learning tasks that require U-shaped behavior? All notions considered are learning in the limit from positive data. We present results about the necessity of U-shaped learning in classical models of learning as well as in models with bounds on the memory of the learner. The pattern emerges that, for parameterized, cognitively relevant learning criteria, beyond very few initial parameter values, U-shapes are necessary for full learning power! We discuss the possible relevance of the above results for the Cognitive Science debate about learning models as well as directions for future research.

Adult Onset Still's Disease Presenting with Acute Respiratory Distress Syndrome: Case Report and Review of the Literature.

INTRODUCTION: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fevers, and arthralgias. Pulmonary involvement has been reported rarely in AOSD, but acute respiratory distress syndrome (ARDS) is extremely rare and potentially fatal and must be recognized as potential manifestation of underlying AOSD. METHODS: We present a case of AOSD manifested by ARDS and review the previously reported cases in Medline/Pub med. RESULTS: Including this case, 19 cases of AOSD complicated with ARDS have been reported in the literature. CONCLUSIONS: It is important to recognize ARDS as a manifestation of AOSD so that proper diagnostic and therapeutic management can be initiated promptly.

Computability-theoretic learning complexity.

Initially discussed are some of Alan Turing's wonderfully profound and influential ideas about mind and mechanism-including regarding their connection to the main topic of the present study, which is within the field of computability-theoretic learning theory. Herein is investigated the part of this field concerned with the algorithmic, trial-and-error inference of eventually correct programs for functions from their data points. As to the main content of this study: in prior papers, beginning with the seminal work by Freivalds et al. in 1995, the notion of intrinsic complexity is used to analyse the learning complexity of sets of functions in a Gold-style learning setting. Herein are pointed out some weaknesses of this notion. Offered is an alternative based on epitomizing sets of functions-sets that are learnable under a given learning criterion, but not under other criteria that are not at least as powerful. To capture the idea of epitomizing sets, new reducibility notions are given based on robust learning (closure of learning under certain sets of computable operators). Various degrees of epitomizing sets are characterized as the sets complete with respect to corresponding reducibility notions! These characterizations also provide an easy method for showing sets to be epitomizers, and they are then employed to prove several sets to be epitomizing. Furthermore, a scheme is provided to generate easily very strong epitomizers for a multitude of learning criteria. These strong epitomizers are the so-called self-learning sets, previously applied by Case & Kötzing in 2010. These strong epitomizers can be easily generated and employed in a myriad of settings to witness with certainty the strict separation in learning power between the criteria so epitomized and other not as powerful criteria!

Serum cardiac troponin T, but not troponin I, is elevated in idiopathic inflammatory myopathies.

OBJECTIVE: To study the association of serum cardiac troponin T (cTnT) and cardiac troponin I (cTnI) with creatine kinase (CK) in patients with idiopathic inflammatory myopathies (IIM). METHODS: We performed a retrospective study on patients with IIM followed by the rheumatology service of a county hospital from 2004 to 2008. Patients with myocardial ischemia and/or with renal failure were excluded. Clinical data including electromyogram, muscle biopsy, and CK, cTnT and cTnI were recorded. Patients who had simultaneous analysis of CK and cardiac troponin (cTnT or cTnI) levels were studied. CK levels were correlated with cTnT and cTnI by chi-square test and Spearman correlation. RESULTS: We identified 49 patients with IIM (69 observations) who satisfied our inclusion criteria. The primary diagnosis was polymyositis in 23, dermatomyositis in 16, and myositis associated with connective tissue disease in 10 patients. There were 33/49 women with average age 45.8 years. Twenty-eight patients with IIM had simultaneous CK and cTnT values assayed. Of those patients, 18/23 with elevated CK also had elevated cTnT, and 5/5 patients with normal CK levels had normal cTnT levels (p = 0.005). In 41 patients with IIM who had simultaneous CK and cTnI levels assayed, only 1/29 with elevated CK had elevated cTnI, and 12/12 patients with normal CK had normal cTnI (p = 0.5). CK correlated strongly with the cTnT (r = 0.62, p = 0.001) but did not correlate with cTnI. CONCLUSION: Elevated cTnT, but not cTnI, was highly associated with CK in patients with IIM despite the absence of myocardial ischemia.

Every employee an owner. Really.

Surveys indicate that when new rules on expensing stock options take effect, many companies are likely to limit the number of employees who can receive equity compensation. But companies that reserve equity for executives are bound to suffer in the long run. Study after study proves that broad-based ownership, when done right, leads to higher productivity, lower workforce turnover, better recruits, and bigger profits. "Done right" is the key. Here are the four most important factors in implementing a broad-based employee equity plan: A significant portion of the workforce--generally, most of the full-time people--must hold equity; employees must think the amounts they hold can significantly improve their financial prospects; managerial practices and policies must reinforce the plan; and employees must feel a true sense of company ownership. Those factors add up to an ownership culture in which employees' interests are aligned with the company's. The result is a workforce that is loyal, cooperative, and willing to go above and beyond to make the organization successful. A wide variety of companies have recorded exceptional business performance with the help of employee-ownership programs supported by management policies. The authors examine two: Science Applications International, a research and development contractor, and Scot Forge, which shapes metal and other materials for industrial machinery. At both companies, every employee with a year or so of service holds equity, and employees who stay on can accumulate a comfortable nest egg. Management's sharing of financial information reinforces workers' sense of ownership. So does the expectation that employees will accept the responsibilities of ownership. Workers with an ownership stake internalize their responsibilities and feel they have an obligation not only to management but to one another.

Five hundred sixty-five triples of chicken, human, and mouse candidate orthologs.

The Human Genome Project has provided abundant gene sequence information on human and important model organisms. The chicken is well positioned from an evolutionary standpoint to serve as a link between higher and lower organisms, particularly mammals, and amphibia and fish. In this study we used stringent criteria to select 565 triples of chicken, human, and mouse candidate orthologs. We analyze the sequences with respect to nucleotide and amino acid similarities. This analysis also allows measurement of evolutionary distances of different proteins. We found that chicken-human and chicken-mouse sequence identities are highly correlated; similarly for chicken-human and chicken-mouse evolutionary distances. With chicken as the out-group, we found that mouse has a higher substitution rate than human, supporting the generation-time effect hypothesis. We also described the transversion bias, which is the preference for some transversions than others in nucleotide substitutions. We demonstrated that there are statistically significant properties in the differences of orthologous sequences. The differential patterns, in combination with sequence similarity analysis, may lead to the identification of genes that are very divergent from the mammalian orthologs.

Asymmetric knee loading in advanced unilateral hip osteoarthritis.

OBJECTIVE: Subjects with unilateral end-stage hip osteoarthritis (OA) who undergo total hip replacement (THR) preferentially require subsequent replacement of the contralateral knee compared with the ipsilateral knee. We investigated whether this nonrandom, preferential evolution of lower extremity OA from the hip to the contralateral knee joint may be related to asymmetries in dynamic joint loading at the knees, particularly the peak external knee adduction moment, which has been associated with the progression of knee OA. METHODS: Gait analysis was performed on 50 subjects who were preoperative for unilateral THR. Twenty-two of these subjects were reevaluated postoperatively 10-23 months after undergoing successful THR. At each analysis, dynamic joint loads in the contralateral knee were compared with those in the ipsilateral knee. RESULTS: Prior to THR, the peak external knee adduction moment and peak medial compartment load were significantly higher in the contralateral knee. This asymmetry persisted after THR. CONCLUSION: Subjects with unilateral end-stage hip OA preferentially require subsequent replacement of the contralateral knee, as compared with the ipsilateral knee. Among patients with unilateral end-stage hip OA, the contralateral knee is subjected to higher dynamic joint loads than is the ipsilateral knee, and this asymmetric loading persists long after subjects have undergone successful THR. Biomechanical factors appear to be involved in the multiarticular evolution of OA of the lower extremities.

Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium.

BACKGROUND: Recommendations state that acetaminophen should be used in preference to nonsteroidal anti-inflammatory drugs in the initial treatment of symptomatic osteoarthritis (OA) of the hip or knee, because of lesser toxicity and the pervasive belief that acetaminophen is not only effective in treating OA pain but is of equal analgesic efficacy as nonsteroidal anti-inflammatory drugs. METHODS: This was a randomized, double-blind, placebo-controlled trial of diclofenac sodium, 75 mg twice daily, vs acetaminophen, 1000 mg 4 times daily, in 82 subjects with symptomatic OA of the medial knee. Osteoarthritis was quantitated radiographically, and subjects met stringent baseline pain criteria. The primary evaluation of efficacy used the Western Ontario and McMaster Universities Osteoarthritis Index, with evaluations at screening, baseline, and 2 and 12 weeks after treatment. Intention-to-treat analysis was used. RESULTS: Twenty-five subjects were randomized to diclofenac, 29 to acetaminophen, and 28 to placebo. The groups were closely matched for age, sex, body mass index, prior use of OA medications, baseline pain, and radiographic features. At 2 and 12 weeks, clinically and statistically significant (P<.001) improvements were seen in the diclofenac-treated group; however, no significant improvements were seen in the acetaminophen-treated group (P =.92 at 2 weeks and.19 at 12 weeks). Stratification of subjects according to baseline pain, prestudy OA medication, and radiographic grade showed no clear pattern of preferential response to diclofenac, and did not reveal a subset of subjects who responded to acetaminophen. CONCLUSIONS: Diclofenac is effective in the symptomatic treatment of OA of the knee, but acetaminophen is not. A review of the literature reveals that there is scanty published evidence for a therapeutic effect of acetaminophen relative to placebo in patients with OA of the knee, because most published studies use active comparators (ie, nonsteroidal anti-inflammatory drugs) only. The advocacy of acetaminophen use in subjects with OA of the knee should be reconsidered pending further placebo-controlled studies.

Nonrandom evolution of end-stage osteoarthritis of the lower limbs.

OBJECTIVE: Patients with unilateral hip or knee replacements for end-stage osteoarthritis (OA) are at high risk for future progression of OA in other joints of the lower extremities, often requiring additional joint replacements. Although the risks of future surgery in the contralateral cognate joints (i.e., contralateral hip replacement after an initial hip replacement) have been evaluated, the evolution of end-stage hip OA to OA involving the knee joints, and vice versa (i.e., noncognate progression) has not been investigated. Because characterization of OA progression in noncognate joints may shed light on the pathogenesis of multijoint OA, we investigated the pattern of evolution of end-stage lower extremity OA in a large, clinical cohort. METHODS: Total joint replacement (TJR) was selected as a marker of end-stage OA, and a database comprising all lower extremity TJRs performed at a large referral center between 1981 and 2001 was accessed. Of the 5,894 patients identified, 486 patients with idiopathic OA who underwent hip replacement and 414 who underwent initial knee replacement were analyzed to determine the relative likelihood of subsequent TJRs. Patients with the systemic inflammatory arthropathy, rheumatoid arthritis (RA), were evaluated as a control population because RA progression is not considered to be a primarily mechanically mediated process. RESULTS: The contralateral cognate joint was the most common second joint to undergo replacement in both the OA and the RA groups. However, in OA patients for whom the second TJR was in a noncognate joint, that joint was >2-fold more likely to be on the contralateral limb than on the ipsilateral limb (hip to knee P < 0.001; knee to hip P = 0.013). In contrast, among the RA cohort, the evolution was random and no laterality for noncognate TJR was observed at either the hip or the knee (P = 0.782). CONCLUSION: This characterization of end-stage lower extremity OA demonstrates that the disease evolves nonrandomly; after 1 joint is replaced, the contralateral limb is significantly more likely to show progression of OA than is the ipsilateral limb. Thus, OA in 1 weight-bearing joint appears to influence the evolution of OA in other joints. The absence of such laterality in RA suggests that OA progression may be mediated by extrinsic factors such as altered joint loading.