Strength through defects: A novel Bayesian approach for the optimization of architected materials.

We use a previously unexplored Bayesian optimization framework, "evolutionary Monte Carlo sampling," to systematically design the arrangement of defects in an architected microlattice to maximize its strain energy density before undergoing catastrophic failure. Our algorithm searches a design space with billions of 4 × 4 × 5 3D lattices, yet it finds the global optimum with only 250 cost function evaluations. Our optimum has a normalized strain energy density 12,464 times greater than its commonly studied defect-free counterpart. Traditional optimization is inefficient for this microlattice because (i) the design space has discrete, qualitative parameter states as input variables, (ii) the cost function is computationally expensive, and (iii) the design space is large. Our proposed framework is useful for architected materials and for many optimization problems in science and elucidates how defects can enhance the mechanical performance of architected materials.

The Israel Family Court - Therapeutic jurisprudence and jurisprudential therapy from the start.

Based on the recommendations of a commission set up to review the handling of Family Law cases in Israel, the Family Courts Law 5755-1995 included a revolutionary provision - that a Social Services Unit, staffed by senior social workers, would be an integral part of each Family Court. Their mandate includes giving assessment, advice and assistance services to litigants and to the court, and this provision has been broadly interpreted, to include mediation and referrals for therapy. The activities of the Unit are confidential and free of charge to the parties. More recently the Units were given the task of seeing children whose future is the subject of litigation, to find out their needs and views; and also to serve as the agency which parties who want to start proceedings are required to attend, in order to receive information about the effect of proceedings on their children and advice about alternative dispute resolution to avoid litigation. The resulting synergy between the social workers and the Judges ensures that the needs of all those involved are met in a therapeutic fashion where this is necessary and possible, alongside the judicial powers to make orders as needed. Thus unnecessary suffering can be mitigated.

In vivo assessment of NS1-truncated influenza virus with a novel SLSYSINWRH motif as a self-adjuvanting live attenuated vaccine.

Mutants of influenza virus that encode C-terminally truncated NS1 proteins (NS1-truncated mutants) characteristically induce high interferon responses. The dual activity of interferon in blocking virus replication and enhancing the development of adaptive immune responses makes these mutants promising as self-adjuvanting live-attenuated influenza vaccine (LAIV) candidates. Yet, among the NS1-truncated mutants, the length of NS1 is not directly correlated with the interferon-inducing efficiency, the level of attenuation, or effectiveness as LAIV. Using quantitative in vitro biologically active particle subpopulation analysis as a tool to identify potential LAIV candidates from a pool of NS1-truncated mutants, we previously predicted that a NS1-truncated mutant pc2, which was less effective as a LAIV in chickens, would be sufficiently effective as a LAIV in mammalian hosts. In this study, we confirmed that pc2 protected mice and pigs against heterologous virus challenge in terms of preventing clinical signs and reducing virus shedding. pc2 expresses a unique SLSYSINWRH motif at the C-terminus of its truncated NS1. Deletion of the SLSYSINWRH motif led to ~821-fold reduction in the peak yield of type I interferon induced in murine cells. Furthermore, replacement of the SLSYSINWRH motif with the wildtype MVKMDQAIMD sequence did not restore the interferon-inducing efficiency. The diminished interferon induction capacity in the absence of the SLSYSINWRH motif was similar to that observed in other mutants which are less effective LAIV candidates. Remarkably, pc2 induced 16-fold or more interferon in human lung and monkey kidney cells compared to the temperature-sensitive, cold-adapted Ann Arbor virus that is currently used as a master backbone for LAIVs such as FluMist. Although the mechanism by which the SLSYSINWRH motif regulates the vaccine properties of pc2 has not been elucidated, this motif has potential use in engineering self-adjuvanting NS1-truncated-based LAIVs.

Three-dimensional vortices generated by self-replication in stably stratified rotating shear flows.

A previously unknown instability creates space-filling lattices of 3D vortices in linearly stable, rotating, stratified shear flows. The instability starts from an easily excited critical layer. The layer intensifies by drawing energy from the background shear and rolls up into vortices that excite new critical layers and vortices. The vortices self-similarly replicate to create lattices of turbulent vortices. The vortices persist for all time. This self-replication occurs in stratified Couette flows and in the dead zones of protoplanetary disks where it can destabilize Keplerian flows.

Influenza virus subpopulations: interferon induction-suppressing particles require expression of NS1 and act globally in cells; UV irradiation of interferon-inducing particles blocks global shut-off and enhances interferon production.

Influenza virus populations contain several subpopulations of noninfectious biologically active particles that are measured by the unique phenotypes they express. Two of these subpopulations were studied: (1) interferon (IFN)-inducing particles (IFP) and (2) IFN induction-suppressing particles (ISP). ISP are dominant in cells coinfected with one or more IFP; they completely suppress IFN production in cells otherwise programmed to induce it. Influenza virus ISP were shown to act in host cells in a nonspecific and global manner, suppressing IFN induction independent of the family of viruses serving as IFN inducers. ISP must be present within the first 3 h of coinfection with IFP to be maximally effective; by 7 hpi IFN induction/production is refractory to the action of superinfecting ISP. UV target and thermal inactivation analyses revealed that ISP activity was dependent solely on the expression of the NS gene. Low doses of UV radiation enhanced by ∼10-fold the already high IFN-inducing capacity of a virus that expressed truncated NS1. There was no change in the number of IFP, implying that the production of IFN/cell had increased. We postulated that preventing degradation of cellular RNA pol II by viral polymerase prolonged the transcription of cellular mRNA, including IFN mRNA, to enhance the IFN-inducing capacity of the cell without any increase in the number of IFP. These studies point to the dueling roles of IFP and ISP in modulating IFN induction/production, the former activity being critical to the efficacy of live attenuated influenza vaccines.

Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency.

Reassortment of influenza A viruses is known to affect viability, replication efficiency, antigenicity, host range, and virulence, and can generate pandemic strains. In this study, we demonstrated that the specific exchange of the NS gene segment from highly pathogenic A/HK/156/97 (H5N1) [E92 or E92D NS1] virus for the cognate NS gene segment of A/PR/834(H1N1) [D92 NS1] virus did not cause a significant change in the sizes of infectious particle subpopulations. However, it resulted in 2 new phenotypic changes: (1) de novo generation of large subpopulations of defective-interfering particles (DIPs); and (2) enhancement of interferon (IFN)-inducing particle efficiency leading to an order of magnitude or higher quantum (peak) yield of IFN in both avian and mammalian cells. These changes were attributed to loss of function of the H5N1-NS gene products. Most notably, the NS exchange obliterated the usual IFN-induction-suppressing capacity associated with expression of full-size NS1 proteins, and hence functionally mimicked deletions in the NS1 gene. The loss of NS1-mediated suppression of IFN induction, de novo generation of DIPs, and the concomitant enhancement of IFN-inducing particle efficiency suggest that in an attenuated background, the H5N1-NS could be used to formulate a self-adjuvanting live attenuated influenza vaccine similar to viruses with deletions in the NS1 gene.

Inflammation in COPD: implications for management.

Chronic obstructive pulmonary disease (COPD) is recognized by the Global Initiative for Chronic Obstructive Lung Disease guidelines as an inflammatory disease state, and treatment rationales are provided accordingly. However, not all physicians follow or are even aware of these guidelines. Research has shown that COPD inflammation involves multiple inflammatory cells and mediators and the underlying pathology differs from asthma inflammation. For these reasons, therapeutic agents that are effective in asthma patients may not be optimal in COPD patients. COPD exacerbations are intensified inflammatory events compared with stable COPD. The clinical and systemic consequences believed to result from the chronic inflammation observed in COPD suggest that inflammation intensity is a key factor in COPD and exacerbation severity and frequency. Although inhaled corticosteroids are commonly used and are essential in asthma management, their efficacy in COPD is limited, with only a modest effect at reducing exacerbations. The importance of inflammation in COPD needs to be better understood by clinicians, and the differences in inflammation in COPD versus asthma should be considered carefully to optimize the use of anti-inflammatory agents.

The CHOICE survey: high rates of persistent and uncontrolled asthma in the United States.

BACKGROUND: Surveys have consistently shown that many patients with asthma do not have their disease well controlled. OBJECTIVES: The CHOICE (Comprehensive Survey of Healthcare Professionals and Asthma Patients Offering Insight on Current Treatment Gaps and Emerging Device Options) survey was designed to evaluate the current status of inhalation devices used in asthma treatment, but questions also were included about asthma severity and control. METHODS: A total of 1,000 patients with asthma were interviewed about their use of inhalation devices and asthma-related burden, medication use, and hospital/emergency care. Based on the responses to these questions, asthma severity and control were categorized using methods established in the Expert Panel Report III (EPR 3). RESULTS: Almost half (490) of the patients with asthma participating in the CHOICE survey were not using controller medications. Most of those not using controllers (79%) had persistent asthma; 47% had either mild or moderate persistent asthma. Of those on controllers (510), only 14.3% were well controlled. Acute care utilization was greater for patients with persistent asthma than those with intermittent asthma and for patients with not well and poorly controlled asthma than those with well-controlled asthma. CONCLUSION: The CHOICE survey is particularly pertinent clinically, because it demonstrates for the first time, using EPR 3 methods, the current extent of poor asthma control in the United States. This situation falls far short of national asthma management targets.

Influenza virus interferon-inducing particle efficiency is reversed in avian and mammalian cells, and enhanced in cells co-infected with defective-interfering particles.

Naturally selected variants of influenza virus encoding truncated NS1 proteins were tested in chickens as candidate live-attenuated influenza vaccines. Their effectiveness correlated with the amount of interferon (IFN) induced in chicken cells. Effective variants induced large amounts of IFN and contained subpopulations with high ratios of defective-interfering particles:IFN-inducing particles (DIP:IFP). Ineffective variants induced less IFN and contained lower ratios of DIP:IFP. Unexpectedly, there was a reversal of phenotypes in mammalian cells. Variants that induced low amounts of IFN and had low DIP:IFP ratios in chicken cells were excellent IFN inducers with high DIP:IFP ratios in mammalian cells, and vice versa. The high DIP:IFP ratios and computer-simulated dynamics of infection suggested that DIP, as an individual particle, did not function as an IFP. The higher efficiency of IFPs in the presence of DIPs was attributed to reduced amounts of newly synthesized viral polymerase known to result from out-competition by defective-interfering RNAs, and the subsequent failure of that polymerase to turn-off cellular mRNA transcription-including IFN-mRNA.

Influenza virus: a single noninfectious interferon induction-suppressing particle blocks expression of interferon-inducing particles.

The interferon (IFN)-inducing capacity of influenza virus plays a significant role in the efficacy of candidate live attenuated influenza vaccines (LAIVs). IFN is induced by a subpopulation of noninfectious biologically active particles (niBAPs) that can be defined and quantified as IFN-inducing particles (IFPs). When chicken embryonic cells were infected with increasing multiplicities of IFP (m(ifp)), the amount of IFN produced was that expected from a Poisson distribution of cells infected with ≥1 IFP. Problematically, some isolates of influenza virus induced less IFN than expected at higher m(ifp). We postulated that these stocks contained another subpopulation of niBAP, IFN induction-suppressing particles (ISPs). A single ISP was assumed capable of preventing IFN production completely in cells coinfected with IFP. Virus stocks were reconstructed to contain a wide range of ratios of IFP:ISP and used to generate IFN-induction dose-response curves. The deviation of the observed yields of IFN from those expected if the virus stock consisted only of IFP fits well the results expected from a formulation of the Poisson distribution that provides the fraction of IFP-infected cells expected to become coinfected with ISP, and hence not yield IFN, as the ratio IFP:ISP decreases. The ideal LAIV might be thought to contain little or no ISP so as to maximize IFN production; however, the most effective LAIV appear to regulate the production of IFN. Thus, it is possible that an optimal ratio of IFP:ISP may exist to produce more effective LAIV, an event that may sometimes occur in nature, or be reconstructed.

Effects of respiratory cycle and body position on quantitative pulmonary perfusion by MRI.

PURPOSE: To evaluate the performance of lung perfusion imaging using two-dimensional (2D) first pass perfusion MRI and a quantitation program based on model-independent deconvolution algorithm. MATERIALS AND METHODS: In eight healthy volunteers 2D first pass lung perfusion was imaged in coronal planes using a partial Fourier saturation recovery stead state free precession (SSFP) technique with a temporal resolution of 160 ms per slice acquisition. The dynamic signal in the lung was measured over time and absolute perfusion calculated based on a model-independent deconvolution program. RESULTS: In the supine position mean pulmonary perfusion was 287 ± 106 mL/min/100 mL during held expiration. It was significantly reduced to 129 ± 68 mL/min/100 mL during held inspiration. Similar differences due to respiration were observed in prone position with lung perfusion much greater during expiration than during inspiration (271 ± 101 versus 99 ± 38 mL/min/100 mL (P < 0.01)). There was a linear increase in pulmonary perfusion from anterior to posterior lung fields in supine position. The perfusion gradient reversed in the prone position with the highest perfusion in anterior lung and the lowest in posterior lung fields. CONCLUSION: Lung perfusion imaging using a 2D saturation recovery SSFP perfusion MRI coupled with a model-independent deconvolution algorithm demonstrated physiologically consistent dynamic heterogeneity of lung perfusion distribution.

Jupiter's zonal winds: are they bands of homogenized potential vorticity organized as a monotonic staircase?

The east-west striped pattern of clouds in Jupiter's weather layer is accompanied by a zonal flow containing 12 eastward-going jet streams alternating in latitude with westward-going jet streams. Based on theory, simulation and observations of the Earth's oceans and atmosphere, it is conjectured that Jupiter's weather layer is made of bands of constant potential vorticity (PV), where the interfaces between bands are at the latitudes of the maxima of the eastward-going jet streams. It is speculated that the mixing of PV on Jupiter is analogous to the mixing of salt in the ocean by the Phillips effect, which causes the salt density to form a monotonic 'staircase'. It is hypothesized that the PV in Jupiter's weather layer is also a staircase, decreasing from north to south. PV is a function of vorticity, as well as parameters with unknown values, e.g. the vertical stratification and the zonal flow beneath the observable weather layer. Therefore, these hypotheses cannot be tested directly. Using an atmospheric model that contains these unknown parameters, we solved the inverse problem and found values of the unknown parameters (and their uncertainties) that best fit Jovian observations. The unknown parameters influence how the zonal flow interacts with large vortices, e.g. the Great Red Spot (GRS; the largest and longest-lived Jovian vortex, centred at 23° S) and the Oval BA (the second largest vortex, centred at 33° S). Although we found that the PV distribution is approximately piecewise-constant and that the peaks of the eastward-going jet streams are at the latitudes of PV interfaces, there is also a PV interface at 20° S, where there is a westward-going jet stream. We find that the zonal PV is not a monotonic staircase due to the 'backwards' interface at 20° S. We show that this backwards interface is necessary to make the GRS nearly round, and that without that interface, the Red Spot would be highly elongated in the east-west direction and probably unstable.

In vitro analysis of virus particle subpopulations in candidate live-attenuated influenza vaccines distinguishes effective from ineffective vaccines.

Two effective (vac+) and two ineffective (vac-) candidate live-attenuated influenza vaccines (LAIVs) derived from naturally selected genetically stable variants of A/TK/OR/71-delNS1[1-124] (H7N3) that differed only in the length and kind of amino acid residues at the C terminus of the nonstructural NS1 protein were analyzed for their content of particle subpopulations. These subpopulations included total physical particles (measured as hemagglutinating particles [HAPs]) with their subsumed biologically active particles of infectious virus (plaque-forming particles [PFPs]) and different classes of noninfectious virus, namely, interferon-inducing particles (IFPs), noninfectious cell-killing particles (niCKPs), and defective interfering particles (DIPs). The vac+ variants were distinguished from the vac- variants on the basis of their content of viral subpopulations by (i) the capacity to induce higher quantum yields of interferon (IFN), (ii) the generation of an unusual type of IFN-induction dose-response curve, (iii) the presence of IFPs that induce IFN more efficiently, (iv) reduced sensitivity to IFN action, and (v) elevated rates of PFP replication that resulted in larger plaques and higher PFP and HAP titers. These in vitro analyses provide a benchmark for the screening of candidate LAIVs and their potential as effective vaccines. Vaccine design may be improved by enhancement of attributes that are dominant in the effective (vac+) vaccines.

International classification of disease coding for obstructive lung disease: does it reflect appropriate clinical documentation?

International Classification of Disease coding is widely used by physicians, hospitals, health-care payers, and governments to assess the health of populations and as a means of reimbursement for medical care based on diagnosis and severity of illness. The current classification system, International Classification of Diseases, 9th ed (ICD-9), will soon be replaced by International Classification of Diseases, 10th ed (ICD-10). When the codes that relate to COPD and asthma are examined, the clinical relevance of the categories in International Classification of Disease coding must be questioned. In the future, a more simplified terminology that is consistent with clinical usage could improve accuracy and ease of coding. At present, however, clinicians should become familiar with the present ICD-9 and future ICD-10 codes so that their descriptions of illnesses in the medical records more accurately reflect current coding terminology.

Lipopolysaccharide: a potent inhibitor of viral-mediated type-I interferon induction.

During the course of codifying low pathogenicity avian influenza, viruses were tested for their capacity to induce type-I interferon (IFN) and to measure their content of IFN induction-suppressing particles (ISP). One isolate caused a >10-fold reduction in the yield of IFN from chicken embryonic cells co-infected with a virus that normally induces high yields of IFN. The apparent content of ISP was calculated to be approximately 100-fold higher than the number of physical particles of virus measured as hemagglutinating particles. This unrealistic interpretation prompted us to test for a soluble IFN induction-suppressing activity in the allantoic fluid freed of the virus by centrifugation. Indeed, the IFN induction-suppressing activity remained in the virus-free supernatant. The original virus stock subsequently was found to be contaminated with a Gram-negative bacterium, leading us to test lipopolysaccharide (LPS) as the putative IFN induction suppressor. Pure LPS mimicked in a similar dose-dependent manner the IFN induction-suppressing activity of the original allantoic fluid-derived virus, and the allantoic fluid freed of all virus and bacteria. The inhibition of viral-mediated type-I IFN induction by LPS was observed for viruses from 3 different families. These observations suggest that exposure of a host to endotoxin may compromise the IFN induction response of the innate immune system and thus exacerbate virus infection.

Dynamics of biologically active subpopulations of influenza virus: plaque-forming, noninfectious cell-killing, and defective interfering particles.

The dynamic changes in the temporal appearance and quantity of a new class of influenza virus, noninfectious cell-killing particles (niCKP), were compared to defective interfering particles (DIP). After a single high-multiplicity passage in MDCK cells of an egg-derived stock that lacked detectable niCKP or DIP, both classes of particles appeared in large numbers (>5 x 10(8)/ml), and the plaque-forming particle (PFP) titer dropped approximately 60-fold. After two additional serial high-multiplicity passages the DIP remained relatively constant, the DIP/niCKP ratio reached 10:1, and the PFP had declined by about 10,000-fold. Together, the niCKP and DIP subpopulations constituted ca. 20% of the total hemagglutinating particle population in which these noninfectious biologically active particles (niBAP) were subsumed. DIP neither killed cells nor interfered with the cell-killing (apoptosis-inducing) activity of niCKP or PFP (infectious CKP), even though they blocked the replication of PFP. Relative to the UV-target of approximately 13,600 nucleotides (nt) for inactivation of PFP, the UV target for niCKP was approximately 2,400 nt, consistent with one of the polymerase subunit genes, and that for DIP was approximately 350 nt, consistent with the small DI-RNA responsible for DIP-mediated interference. Thus, niCKP and DIP are viewed as distinct particles with a propensity to form during infection at high multiplicities. These conditions are postulated to cause aberrations in the temporally regulated replication of virus and its packaging, leading to the production of niBAP. DIP have been implicated in the virulence of influenza virus, but the role of niCKP is yet unknown.

Development and validation of the Chronic Obstructive Pulmonary Disease Assessment Questionnaire (COPD-AQ).

AIMS: To develop a practical patient-completed chronic obstructive pulmonary disease assessment questionnaire (COPD-AQ) to improve COPD assessment and management in primary care, based on the concept of COPD stability. METHODS: An Expert Working Group defined parameters of COPD stability and a 10-item Physician's Global Assessment was established. A 21-item COPD-AQ was developed and validated in a cross-sectional, non-randomised study of patients with COPD (n=395). Items most discriminative of stability status (stable/unstable) were selected to produce a 5-item COPD-AQ, which was then validated. RESULTS: In the development sample, internal consistency reliability of the 5-item COPD-AQ was 0.74 (n=296). The COPD-AQ discriminated between stability groups based on physician assessment (F=44.26; p<0.0001) and post-bronchodilator spirometry measures (F=2.92; p<0.05). A questionnaire score >20 (range: 5.0-25.0) had a specificity of 82.9% and sensitivity of 64.7%. CONCLUSIONS: The 5-item COPD-AQ proved a practical tool for assessing COPD status and was sufficiently simple for routine clinical use. However, overall validation was limited by small numbers of patients in the validation sample. Difficulties also existed over using the term 'stability' to define COPD status. COPD-AQ was not progressed further, but this work will prove valuable in the future development of a global questionnaire to improve COPD management in primary care.

Selection rules for the nonlinear interaction of internal gravity waves.

Two intersecting beams of internal gravity waves will generically create two wave packets by nonlinear interaction. The frequency of one packet will be the sum and that of the other packet will be the difference of the frequencies of the intersecting beams. In principle, each packet should form an "X" pattern, or "St. Andrew's cross" consisting of four beams outgoing from the point of intersection. Here we derive selection rules and show that most of the expected nonlinear beams are forbidden. These rules can also be applied to the reflection of a beam from a boundary.

A retrospective randomized study of asthma control in the US: results of the CHARIOT study.

BACKGROUND: The third version of the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report (EPR-3): Guidelines on the Diagnosis and Management of Asthma emphasizes the need to use asthma control rather than patient severity to base adjustments to treatment and ultimately improve patient outcomes. The objectives of the current study were to assess control of patients with moderate-to-severe asthma, examine the natural history of the disease, practice patterns and resource utilization in specialty community practices according to recently reviewed NAEPP guidelines. RESEARCH DESIGN AND METHODS: This analysis represents a retrospective, multicenter, randomized study of 1009 patient charts in sixty United States allergy and pulmonary medicine community practices. The proportion of patients with controlled and uncontrolled asthma over 12 months, prevalence and characteristics of atopy, past asthma history, pulmonary function, medications and treatment patterns, patient and clinical practice characteristics were analyzed. MAIN OUTCOME MEASURES: The primary outcome of interest was asthma control. RESULTS: A total of 365 male and 644 female patients with moderate-to-severe persistent asthma (mean 43.2 +/- 17.1 years) were enrolled. 81.9% of patients were uncontrolled according to recent NAEPP guidelines. Importantly, a greater percentage of patients with moderate asthma vs. severe persistent asthma were uncontrolled (p < 0.0114). Atopy was detected in 92% of patients. Patients with early onset of asthma were associated with control (p < 0.0433). Atopic symptoms, such as allergic rhinitis (p < 0.0130) and rhinosinusitis (p < 0.0476), were associated with uncontrolled asthma. Uncontrolled patients were also associated with more medications (a mean of 4.05 +/- 1.87 medications) than were controlled patients (a mean of 3.40 +/- 1.37 medications (p < 0.0001), although the temporal relationship of this association was not recorded. Limitations may have included patient and/or study site selection bias and difficulty in the process of operationalizing the definitions of control and disease severity. Since the current study only examined patients from specialty practices, the results may not be generalizable to the overall asthma population. CONCLUSIONS: Greater than 80% of asthma patients from specialty practices were uncontrolled with regard to asthma symptoms. Atopic symptoms, such as allergic rhinitis and rhinosinusitis, in addition to a greater number of medications, were associated with uncontrolled asthma. Moreover, patients designated as having asthma of moderate severity were associated with being uncontrolled more than were those with severe asthma (p < 0.0114), which suggests that the former population may not have received adequate assessment of impairment or risk, with subsequent changes in treatment for control of symptoms.