Predicting the emergence of drug-resistant HSV-2: new predictions

BACKGROUND: Mathematical models can be used to predict the emergence and transmission of antiviral resistance. Previously it has been predicted that high usage of antivirals (in immunocompetent populations) to treat Herpes Simplex Virus type 2 (HSV-2) would only lead to fairly low levels of antiviral resistance. The HSV-2 predictions were based upon the assumption that drug-resistant strains of HSV-2 would be less infectious than drug-sensitive strains but that the drug-resistant strains would not be impaired in their ability to reactivate. Recent data suggest that some drug-resistant strains of HSV-2 are likely to be impaired in their ability to reactivate. Objectives: (1) To predict the effect of a high usage of antivirals on the prevalence of drug-resistant HSV-2 under the assumption that drug-resistant strains will be less infectious than drug-sensitive strains of HSV-2 and also have an impaired ability to reactivate. (2) To compare predictions with previous published predictions. METHODS: We generated theoretical drug-resistant HSV-2 strains that were attenuated (in comparison with drug-sensitive strains) in both infectivity and ability to reactivate. We then used a transmission model to predict the emergence and transmission of drug-resistant HSV-2 in the immunocompetent population assuming a high usage of antivirals. RESULTS: Our predictions are an order of magnitude lower than previous predictions; we predict that even after 25 years of high antiviral usage only 5 out of 10,000 immunocompetent individuals will be shedding drug-resistant virus. Furthermore, after 25 years, 52 cases of HSV-2 would have been prevented for each prevalent case of drug-resistant HSV-2. CONCLUSIONS: The predicted levels of drug-resistant HSV-2 for the immunocompetent population are so low that it seems unlikely that cases of drug-resistant HSV-2 will be detected

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Rare coding SNP in DZIP1 gene associated with late-onset sporadic Parkinson's disease

We present the first application of the hypothesis-rich mathematical theory to genome-wide association data. The Hamza et al. late-onset sporadic Parkinson's disease genome-wide association study dataset was analyzed. We found a rare, coding, non-synonymous SNP variant in the gene DZIP1 that confers increased susceptibility to Parkinson's disease. The association of DZIP1 with Parkinson's disease is consistent with a Parkinson's disease stem-cell ageing theory.Comment: 14 page

Classification of non-Riemannian doubled-yet-gauged spacetime

Assuming $\mathbf{O}(D,D)$ covariant fields as the `fundamental' variables, Double Field Theory can accommodate novel geometries where a Riemannian metric cannot be defined, even locally. Here we present a complete classification of such non-Riemannian spacetimes in terms of two non-negative integers, $(n,\bar{n})$, $0\leq n+\bar{n}\leq D$. Upon these backgrounds, strings become chiral and anti-chiral over $n$ and $\bar{n}$ directions respectively, while particles and strings are frozen over the $n+\bar{n}$ directions. In particular, we identify $(0,0)$ as Riemannian manifolds, $(1,0)$ as non-relativistic spacetime, $(1,1)$ as Gomis-Ooguri non-relativistic string, $(D{-1},0)$ as ultra-relativistic Carroll geometry, and $(D,0)$ as Siegel's chiral string. Combined with a covariant Kaluza-Klein ansatz which we further spell, $(0,1)$ leads to Newton-Cartan gravity. Alternative to the conventional string compactifications on small manifolds, non-Riemannian spacetime such as $D=10$, $(3,3)$ may open a new scheme of the dimensional reduction from ten to four.Comment: 1+41 pages; v2) Refs added; v3) Published version; v4) Sign error in (2.51) correcte

Smeared versus localised sources in flux compactifications

We investigate whether vacuum solutions in flux compactifications that are obtained with smeared sources (orientifolds or D-branes) still survive when the sources are localised. This seems to rely on whether the solutions are BPS or not. First we consider two sets of BPS solutions that both relate to the GKP solution through T-dualities: (p+1)-dimensional solutions from spacetime-filling Op-planes with a conformally Ricci-flat internal space, and p-dimensional solutions with Op-planes that wrap a 1-cycle inside an everywhere negatively curved twisted torus. The relation between the solution with smeared orientifolds and the localised version is worked out in detail. We then demonstrate that a class of non-BPS AdS_4 solutions that exist for IASD fluxes and with smeared D3-branes (or analogously for ISD fluxes with anti-D3-branes) does not survive the localisation of the (anti) D3-branes. This casts doubts on the stringy consistency of non-BPS solutions that are obtained in the limit of smeared sources.Comment: 23 pages; v2: minor corrections, added references, version published in JHE

Quality and Safety Aspects of Infant Nutrition

Quality and safety aspects of infant nutrition are of key importance for child health, but oftentimes they do not get much attention by health care professionals whose interest tends to focus on functional benefits of early nutrition. Unbalanced diets and harmful food components induce particularly high risks for untoward effects in infants because of their rapid growth, high nutrient needs, and their typical dependence on only one or few foods during the first months of life. The concepts, standards and practices that relate to infant food quality and safety were discussed at a scientific workshop organized by the Child Health Foundation and the Early Nutrition Academy jointly with the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, and a summary is provided here. The participants reviewed past and current issues on quality and safety, the role of different stakeholders, and recommendations to avert future issues. It was concluded that a high level of quality and safety is currently achieved, but this is no reason for complacency. The food industry carries the primary responsibility for the safety and suitability of their products, including the quality of composition, raw materials and production processes. Introduction of new or modified products should be preceded by a thorough science based review of suitability and safety by an independent authority. Food safety events should be managed on an international basis. Global collaboration of food producers, food-safety authorities, paediatricians and scientists is needed to efficiently exchange information and to best protect public health. Copyright (C) 2012 S. Karger AG, Base

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P&lt;0.05) and macrophage (P&lt;0.05) infiltration and microvessel density (P&lt;0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P&lt;0.01), negative hormonal receptor (P&lt;0.10), lower albumin concentrations (P&lt;0.01), increased tumour proliferation (P&lt;0.05), increased tumour microvessel density (P&lt;0.05), the extent of locoregional control (P&lt;0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P&lt;0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

Unique Roles of Mothering and Fathering in Child Anxiety; Moderation by Child’s Age and Gender

We examined the associations between the parenting dimensions autonomy granting, over control, and rejection and children’s anxiety, in relation to parent and child gender and child age. Elementary school-aged children (n = 179, Mage = 10.27, SD = 1.30), adolescents (n = 127, Mage = 15.02, SD = 1.54) and both their parents completed questionnaires on parenting and children’s anxiety. Parenting was more strongly related to child anxiety in elementary school children than in adolescents. Maternal over control was uniquely related to elementary school-aged children’s anxiety whereas paternal over control was more important during adolescence. Opposite to our expectations, we found higher levels of parental autonomy granting to be related to higher levels of anxiety for younger elementary school-aged children (age < 10). For adolescents, the association between paternal over control and anxiety was stronger for older adolescents (age > 15), with higher levels of over control related to higher levels of anxiety. For both elementary school-aged children and adolescents, the associations between parenting and child anxiety did not differ as a function of the child’s gender. If we are to understand the associations between parenting and children’s anxiety, it is important to distinguish parental autonomy granting from parental over control and to consider the role of parent gender and the age of the child