Frictionless bead packs have macroscopic friction, but no dilatancy

The statement of the title is shown by numerical simulation of homogeneously sheared packings of frictionless, nearly rigid beads in the quasistatic limit. Results coincide for steady flows at constant shear rate γ in the limit of small γ and static approaches, in which packings are equilibrated under growing deviator stresses. The internal friction angle ϕ, equal to 5.76 $\pm$ 0.22 degrees in simple shear, is independent on the average pressure P in the rigid limit. It is shown to stem from the ability of stable frictionless contact networks to form stress-induced anisotropic fabrics. No enduring strain localization is observed. Dissipation at the macroscopic level results from repeated network rearrangements, like the effective friction of a frictionless slider on a bumpy surface. Solid fraction Φ remains equal to the random close packing value ≃ 0.64 in slowly or statically sheared systems. Fluctuations of stresses and volume are observed to regress in the large system limit, and we conclude that the same friction law for simple shear applies in the large psystem limit if normal stress or density is externally controlled. Defining the inertia number as I = γ m/(aP), with m the grain mass and a its diameter, both internal friction coefficient $\mu$∗ = tan ϕ and volume 1/Φ increase as powers of I in the quasistatic limit of vanishing I, in which all mechanical properties are determined by contact network geometry. The microstructure of the sheared material is characterized with a suitable parametrization of the fabric tensor and measurements of connectivity and coordination numbers associated with contacts and near neighbors.Comment: 19 pages. Additional technical details may be found in v

The Burden of Trachoma in Ayod County of Southern Sudan

Trachoma, a neglected tropical disease, is the leading cause of infectious blindness and is targeted for global elimination by the year 2020. We conducted a survey in Ayod County of Jonglei State, Southern Sudan, to determine whether blinding trachoma was a public health problem and to plan interventions to control this disease. We found the burden of trachoma in Ayod to be one of the most severe ever documented. Not only were adults affected by the advanced manifestations of the disease as is typical for older age groups, but young children were also affected. At least one person with clinical signs of trachoma was found in nearly every household, and 1 in 3 households had a person with severe blinding trachoma. Characteristics previously identified as risk factors were ubiquitous among surveyed households, but we were unable to identify why trachoma is so severe in this location. Surgical interventions are needed urgently to improve vision and prevent irreversible blindness in children and adults. Mass antibiotic distribution may alleviate current infections and transmission of trachoma may be reduced if communities adopt the behavior of face washing and safe disposal of human waste. Increasing access to improved water sources may not only improve hygiene but also reduce the spread of guinea worm and other water-borne diseases

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use “if somewhat protective” was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) Cmax 30 min after single rectal exposure was 6–10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK–PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK–PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations

Ocular medicines in children: the regulatory situation related to clinical research

<p>Abstract</p> <p>Background</p> <p>Many ocular medications are prescribed for paediatric patients, but the evidence for their rational use is very scant. This study was planned to compare the availability and the licensing status of ocular medications marketed in Italy, the United Kingdom (UK), and the United States of America (USA) related to the amount of published and un-published RCTs testing these drugs in the paediatric population.</p> <p>Methods</p> <p>A quantitative analysis was performed to evaluate the number of ocular medications with a paediatric license in Italy, the UK, and the USA. A literature search was also performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) on ophthalmic pharmacological therapy in children aged < 18 years, published up to December 2010. A search in the international clinical trial registries, the list of paediatric investigation plans (PIPs) approved by European Medicines Agency (EMA), and the table of medicines with new paediatric information approved by Food and Drug Administration (FDA) was also performed.</p> <p>Results</p> <p>In all, of 197 drugs identified, 68 (35%) single drugs are licensed for paediatric use at least in one considered country, while 23 (12%) were marketed in all three countries. More specifically, in Italy 43 single drugs (48% of those marketed) had a paediatric license, while 39 (64%) did in the UK and 22 (54%) did in the USA. Only 13 drugs were marketed with a paediatric license in all countries.</p> <p>The percentage of drugs licensed for paediatric use and for which at least one RCT had been performed ranged between 51% in Italy and 55% in the USA. No published RCTs were found for 11 (48%) drugs licensed for paediatric use in all three countries. In all, 74 (35%) of the retrieved RCTs involved mydriatic/cycloplegic medications.</p> <p>A total of 62 RCTs (56% completed) on 46 drugs were found in the international clinical trial registries. Cyclosporin and bevacizumab were being studied in many ongoing trials. Twenty-six drugs had new paediatric information approved by FDA based on new paediatric clinical trials, while only 4 PIPs were approved by EMA.</p> <p>Conclusions</p> <p>There is a pressing need for further research and clinical development in the pediatric ophthalmic area, where effective up-to-date treatments, and additional research and education on use in children, remain priorities.</p

Active Trachoma and Ocular Chlamydia trachomatis Infection in Two Gambian Regions: On Course for Elimination by 2020?

Trachoma is the leading infectious cause of blindness worldwide, and is mainly found in tropical and poor countries. It is caused by infection of the eyes with the bacterium Chlamydia trachomatis. However, sometimes the clinical signs of disease can be present without infection being detected. Control efforts involve surgery, antibiotic treatment, face washing, and environmental improvement for better hygiene. Surveys of trachoma help countries to know whether and where they should implement control interventions. The Gambia is found in West Africa and has suffered from trachoma for decades. We conducted a survey of two Gambian regions to look at how much trachoma disease and C. trachomatis infection there is in the eyes. We found that although there was enough disease (≥10%) to warrant antibiotic treatment for everyone in the regions, there was nearly no infection (0.3%). This means that using clinical signs alone to make treatment decisions in low prevalence settings like The Gambia can lead to the waste of scarce resources. Our results also suggest that since less than 1% of children are infected with C. trachomatis, The Gambia is on course to achieve the World Health Organization's aim of eliminating blinding trachoma by the year 2020

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10 -12 for SNP rs634990 in Caucasians, and 9.65 × 10 -4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10 -23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10 -2 for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide. © The Author(s) 2012

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia : The CREAM Consortium

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).Peer reviewe

Decentralization and Environment: An Application to Water Policies

By means of a two-jurisdictional model, this paper analyses the optimal division of environmental policymaking functions among the different government levels, identifying the most appropriate level of decentralization in each case. The paper focuses on water resources policies, with an application to Spanish regions during the 1996-2001 period. The estimation of an environmental quality-consumption transformation function allows the implementation of a simulation to find the most efficient policies in the context of water resources