Some properties of the dissipative model of strain-gradient plasticity

A theoretical and computational investigation is carried out of a dissipative model of rate-independent strain-gradient plasticity and its regularization. It is shown that the flow relation, when expressed in terms of the Cauchy stress, is necessarily global. The most convenient approach to formulating the flow relation is through the use of a dissipation function. It is shown, however, that the task of obtaining the dual version, in the form of a normality relation, is a complex one. A numerical investigation casts further light on the response using the dissipative theory in situations of non-proportional loading. The elastic gap, a feature reported in recent investigations, is observed in situations in which passivation has been imposed. It is shown computationally that the gap may be regarded as an efficient path between a load-deformation response corresponding to micro-free boundary conditions, and that corresponding to micro-hard boundary conditions, in which plastic strains are set equal to zero.Comment: 26 pages, 10 figure

Childhood-onset Leber hereditary optic neuropathy

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor

Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Background: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. Methods: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). Findings: Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80). Interpretation: Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care. Funding: The National Health and Medical Research Council of Australia

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

ON THE DETERMINANTS OF LEVERAGED BUYOUT ACTIVITY: A COMPARISON BETWEEN DEVELOPED AND DEVELOPING ECONOMIES

I study Leveraged buyouts (LBOs) internationally over the period 1980-2012. Returns on LBOs are on average higher for developed markets. However, returns of LBOs during high economic growth periods are high for developing nations relative to developed economies. On the other hand returns in developing nations are lower when compared to the returns in developed nations in periods of negative economic growth. During periods of negative economic growth, the returns in developing nations do not compensate for the high risk associated with them. Developing countries are more unstable relative to developed countries during conditions of boom as well as collapse. Exit times for LBO transactions in developing economies are therefore shorter relative to developed economies in periods of high economic growth rate. This is because PE investment firms would like to exit soon and lock in their profits. During periods of negative economic growth rate, the LBOs in developing nations exit sooner. When things go badly in the developing economies, they are magnified multiple times. Hence the PE firms would like to avoid further losses and hence exit sooner. In periods of low or medium economic growth, LBOs in developing economies take longer times to exit. Reputed firms and small firms have higher returns and exit sooner. Club deals have higher returns and exit sooner when compared with single PE firm deals, until the year there was higher government on the motive of club deals. After 2006 there was higher government scrutiny which make club deals take longer time to exit. Club deals in developing economies are on average not profitable and exit sooner

Universally composable zero-knowledge protocol using trusted platform modules

Cryptographic protocols that are established as secure in the Universally Composable (UC) model of security provide strong security assurances even when run in complex environments. Unfortunately, in order to achieve such strong security properties, UC protocols are often impractical, and most non-trivial two-party protocols cannot be secure in the UC model without some sort of external capability (or "setup assumption") being introduced. Recent work by Hofheinz et al provided an important breakthrough in designing realistic universally composable two party protocols, in which they use trusted, tamper proof hardware as a special type of helping functionality which they call a catalyst. Hofheinz et al. use government issued signature cards as a catalyst to design universally composable protocols for zero-knowledge proofs and commitments, but did not give a complete security proof for either protocol. In this thesis, we consider another form of security hardware, Trusted Platform Modules (TPMs), which are more widespread than signature cards and are currently shipped as a part of almost every business laptop or desktop. Trusted Module Platforms are tamper evident devices which support cryptographic functionalities including digital signatures, but have a different key management model from signature cards. In this thesis we consider TPMs as catalysts and describe a universally composable zero knowledge protocol using Trusted Platform Modules. We also present a complete security proof for both the Hofheinz's universally composable zero knowledge protocol from signature cards and our universally composable zero knowledge protocol using TPMs as a catalyst

Methods to estimate link level travel based on spatial effects

Annual Average Daily Traffic (AADT) is used in several planning, roadway design, operational and safety analyses by transportation planners and engineers. Existing methods are very complex and do not adequately address the modeling needs. Errors and inaccuracies in a traditional four-step method get carried to later steps often resulting in incorrect estimates of travel demand. The primary focus of this research is to develop a systematic and simplified methodology to estimate link level travel on roadways. The proposed methodology involves scientific principles and statistical techniques, but bypasses the tedious four-step method. Two spatial methods, first one based on “spatial proximity” and second one based on “spatial weighting”, are proposed to estimate link level travel. While the former method investigates to identify ideal “proximal” distance to capture spatial data, the later method involves application of “spatial weights” that decrease with an increase in distance to integrate spatial data from multiple buffer bandwidths. Generalized Estimating Equations (GEE) models are developed for both the methods using Poisson and Negative Binomial distributions with and without network characteristics to facilitate transportation planning and analysis. Validation of the developed models is carried out using Chi-Square Statistic test. The goodness of fit statistics indicates that Negative Binomial models performed better than Poisson models. Models with network characteristics performed better than models without network characteristics. Model validation results indicate that link level travel can be accurately estimated using both the spatial methods

Nitrated fatty acids reverse cigarette smoke-induced alveolar macrophage activation and inhibit protease activity via electrophilic S-alkylation

Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor γ (PPARγ) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-κB while upregulating those of PPARγ. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARγ knockout mice, pointing to a PPARγ-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs' electrophilic activity, in addition to their role as PPARγ agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease

Eliminating Malaria Vectors.

Malaria vectors which predominantly feed indoors upon humans have been locally eliminated from several settings with insecticide treated nets (ITNs), indoor residual spraying or larval source management. Recent dramatic declines of An. gambiae in east Africa with imperfect ITN coverage suggest mosquito populations can rapidly collapse when forced below realistically achievable, non-zero thresholds of density and supporting resource availability. Here we explain why insecticide-based mosquito elimination strategies are feasible, desirable and can be extended to a wider variety of species by expanding the vector control arsenal to cover a broader spectrum of the resources they need to survive. The greatest advantage of eliminating mosquitoes, rather than merely controlling them, is that this precludes local selection for behavioural or physiological resistance traits. The greatest challenges are therefore to achieve high biological coverage of targeted resources rapidly enough to prevent local emergence of resistance and to then continually exclude, monitor for and respond to re-invasion from external populations

Effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes in low risk pregnancy (the IRIS study): nationwide, pragmatic, multicentre, stepped wedge cluster randomised trial

Objectives To investigate the effectiveness of routine ultrasonography in the third trimester in reducing adverse perinatal outcomes in low risk pregnancies compared with usual care and the effect of this policy on maternal outcomes and obstetric interventions. Design Pragmatic, multicentre, stepped wedge cluster randomised trial. Setting 60 midwifery practices in the Netherlands. Participants 13 046 women aged 16 years or older with a low risk singleton pregnancy. Interventions 60 midwifery practices offered usual care (serial fundal height measurements with clinically indicated ultrasonography). After 3, 7, and 10 months, a third of the practices were randomised to the intervention strategy. As well as receiving usual care, women in the intervention strategy were offered two routine biometry scans at 28-30 and 34-36 weeks’ gestation. The same multidisciplinary protocol for detecting and managing fetal growth restriction was used in both strategies. Main outcome measures The primary outcome measure was a composite of severe adverse perinatal outcomes: perinatal death, Apgar score <4, impaired consciousness, asphyxia, seizures, assisted ventilation, septicaemia, meningitis, bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leucomalacia, or necrotising enterocolitis. Secondary outcomes were two composite measures of severe maternal morbidity, and spontaneous labour and birth. Results Between 1 February 2015 and 29 February 2016, 60 midwifery practices enrolled 13 520 women in mid-pregnancy (mean 22.8 (SD 2.4) weeks’ gestation). 13 046 women (intervention n=7067, usual care n=5979) with data based on the national Dutch perinatal registry or hospital records were included in the analyses. Small for gestational age at birth was significantly more often detected in the intervention group than in the usual care group (179 of 556 (32%) v 78 of 407 (19%), P<0.001). The incidence of severe adverse perinatal outcomes was 1.7% (n=118) for the intervention strategy and 1.8% (n=106) for usual care. After adjustment for confounders, the difference between the groups was not significant (odds ratio 0.88, 95% confidence interval 0.70 to 1.20). The intervention strategy showed a higher incidence of induction of labour (1.16, 1.04 to 1.30) and a lower incidence of augmentation of labour (0.78, 0.71 to 0.85). Maternal outcomes and other obstetric interventions did not differ between the strategies. Conclusion In low risk pregnancies, routine ultrasonography in the third trimester along with clinically indicated ultrasonography was associated with higher antenatal detection of small for gestational age fetuses but not with a reduced incidence of severe adverse perinatal outcomes compared with usual care alone. The findings do not support routine ultrasonography in the third trimester for low risk pregnancies. Trial registration Netherlands Trial Register NTR4367