Compliance with anthelmintic treatment in the neglected tropical diseases control programmes: a systematic review

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An economic evaluation of expanding hookworm control strategies to target the whole community.

Background: The WHO treatment guidelines for the soil-transmitted helminths (STH) focus on targeting children for the control of morbidity induced by heavy infections. However, unlike the other STHs, the majority of hookworm infections are harboured by adults. This untreated burden may have important implications for controlling both hookworm’s morbidity and transmission. This is particularly significant in the context of the increased interest in investigating STH elimination strategies. Methods We used a deterministic STH transmission model and parameter estimates derived from field epidemiological studies to evaluate the impact of child-targeted (2–14 year olds) versus community-wide treatment against hookworm in terms of preventing morbidity and the timeframe for breaking transmission. Furthermore, we investigated how mass treatment may influence the long-term programmatic costs of preventive chemotherapy for hookworm. Results: The model projected that a large proportion of the overall morbidity due to hookworm was unaffected by the current child-targeted strategy. Furthermore, driving worm burdens to levels low enough to potentially break transmission was only possible when using community-wide treatment. Due to these projected reductions in programme duration, it was possible for community-wide treatment to generate cost savings – even if it notably increases the annual distribution costs. Conclusions: Community-wide treatment is notably more cost-effective for controlling hookworm’s morbidity and transmission than the current child-targeted strategies and could even be cost-saving in many settings in the longer term. These calculations suggest that it is not optimum to treat using the same treatment strategies as other STH. Hookworm morbidity and transmission control require community-wide treatment.</p

Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2

Crumbs family proteins are apical transmembrane proteins with ancient roles in cell polarity. Mouse Crumbs2 mutants arrest at midgestation with abnormal neural plate morphology and a deficit of mesoderm caused by defects in gastrulation. We identified an ENU-induced mutation, wsnp, that phenocopies the Crumbs2 null phenotype. We show that wsnp is a null allele of Protein O-glucosyltransferase 1 (Poglut1), which encodes an enzyme previously shown to add O-glucose to EGF repeats in the extracellular domain of Drosophila and mammalian Notch, but the role of POGLUT1 in mammalian gastrulation has not been investigated. As predicted, we find that POGLUT1 is essential for Notch signaling in the early mouse embryo. However, the loss of mouse POGLUT1 causes an earlier and more dramatic phenotype than does the loss of activity of the Notch pathway, indicating that POGLUT1 has additional biologically relevant substrates. Using mass spectrometry, we show that POGLUT1 modifies EGF repeats in the extracellular domain of full-length mouse CRUMBS2. CRUMBS2 that lacks the O-glucose modification fails to be enriched on the apical plasma membrane and instead accumulates in the endoplasmic reticulum. The data demonstrate that CRUMBS2 is the target of POGLUT1 for the gastrulation epithelial-to-mesenchymal transitions (EMT) and that all activity of CRUMBS2 depends on modification by POGLUT1. Mutations in human POGLUT1 cause Dowling-Degos Disease, POGLUT1 is overexpressed in a variety of tumor cells, and mutations in the EGF repeats of human CRUMBS proteins are associated with human congenital nephrosis, retinitis pigmentosa and retinal degeneration, suggesting that O-glucosylation of CRUMBS proteins has broad roles in human health

The J-triplet Cooper pairing with magnetic dipolar interactions

Recently, cold atomic Fermi gases with the large magnetic dipolar interaction have been laser cooled down to quantum degeneracy. Different from electric-dipoles which are classic vectors, atomic magnetic dipoles are quantum-mechanical matrix operators proportional to the hyperfine-spin of atoms, thus provide rich opportunities to investigate exotic many-body physics. Furthermore, unlike anisotropic electric dipolar gases, unpolarized magnetic dipolar systems are isotropic under simultaneous spin-orbit rotation. These features give rise to a robust mechanism for a novel pairing symmetry: orbital p-wave (L=1) spin triplet (S=1) pairing with total angular momentum of the Cooper pair J=1. This pairing is markedly different from both the $^3$He-B phase in which J=0 and the $^3$He-$A$ phase in which $J$ is not conserved. It is also different from the p-wave pairing in the single-component electric dipolar systems in which the spin degree of freedom is frozen

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

CAP defines a second signalling pathway required for insulin-stimulated glucose transport

Insulin stimulates the transport of glucose into fat and muscle cells. Although the precise molecular mechanisms involved in this process remain uncertain, insulin initiates its actions by binding to its tyrosine kinase receptor, leading to the phosphorylation of intracellular substrates. One such substrate is the Cbl protooncogene product(1). Cbl is recruited to the insulin receptor by interaction with the adapter protein CAP, through one of three adjacent SH3 domains in the carboxy terminus of CAP(2). Upon phosphorylation of Cbl, the CAP-Cbl complex dissociates from the insulin receptor and moves to a caveolin-enriched, triton-insoluble membrane fraction(3). Here, to identify a molecular mechanism underlying this subcellular redistribution, we screened a yeast two-hybrid library using the amino-terminal region of CAP and identified the caveolar protein flotillin. Flotillin forms a ternary complex with CAP and Cbl, directing the localization of the CAP-Cbl complex to a lipid raft subdomain of the plasma membrane. Expression of the N-terminal domain of CAP in 3T3-L1 adipocytes blocks the stimulation of glucose transport by insulin, without affecting signalling events that depend on phosphatidylinositol-3-OH kinase. Thus, localization of the Cbl-CAP complex to lipid rafts generates a pathway that is crucial in the regulation of glucose uptake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62940/1/407202a0.pd

Robust optical delay lines via topological protection

Phenomena associated with topological properties of physical systems are naturally robust against perturbations. This robustness is exemplified by quantized conductance and edge state transport in the quantum Hall and quantum spin Hall effects. Here we show how exploiting topological properties of optical systems can be used to implement robust photonic devices. We demonstrate how quantum spin Hall Hamiltonians can be created with linear optical elements using a network of coupled resonator optical waveguides (CROW) in two dimensions. We find that key features of quantum Hall systems, including the characteristic Hofstadter butterfly and robust edge state transport, can be obtained in such systems. As a specific application, we show that the topological protection can be used to dramatically improve the performance of optical delay lines and to overcome limitations related to disorder in photonic technologies.Comment: 9 pages, 5 figures + 12 pages of supplementary informatio

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

Ethnic variations in duration of untreated psychosis: report from the CRIS-FEP study

Objectives:  There is inconsistent evidence on the influence of ethnicity on duration of untreated psychosis (DUP). We investigated ethnic differences in DUP in a large epidemiological dataset of first episode psychosis patients in an inner city area of south London, UK. Methods:  We analysed data on 558 first episode psychosis patients at the South London and Maudsley NHS Trust, between 2010 and 2012. We performed multivariable logistic regression to estimate the odds of a short DUP (≤ 6 months) by ethnic group, controlling for confounders. Results:  There was no evidence that ethnicity is associated with duration of untreated psychosis. However, we found evidence that a short DUP was strongly associated with age, living circumstances, and pathways to care variables (involuntary admission, out of office hour contact, accident and emergency referral, criminal justice agency referral and family involvement in help-seeking). Conversely, a long DUP was associated with report of social isolation, living alone, being single and General Practitioner referral. Conclusion:  Our findings suggest that indicators of social isolation were associated with long DUP. Our data also show that pathways into care characteristics play significant role in DUP. Thus, the challenge of tackling the issue of timely access to EI under the new Access and Waiting Time standard for psychosis requires a multilevel approach, including joint working with communities, public awareness of psychosis, less restrictive referral pathways and adequate resourcing of early intervention for psychosis services. These will go a long way in addressing patients’ needs rather than be determined by service structures

Preoperative Red Cell Distribution Width and 30-day mortality in older patients undergoing non-cardiac surgery: a retrospective cohort observational study

Increased red cell distribution width (RDW) is associated with poorer outcomes in various patient populations. We investigated the association between preoperative RDW and anaemia on 30-day postoperative mortality among elderly patients undergoing non-cardiac surgery. Medical records of 24,579 patients aged 65 and older who underwent surgery under anaesthesia between 1 January 2012 and 31 October 2016 were retrospectively analysed. Patients who died within 30 days had higher median RDW (15.0%) than those who were alive (13.4%). Based on multivariate logistic regression, in our cohort of elderly patients undergoing non-cardiac surgery, moderate/severe preoperative anaemia (aOR 1.61, p = 0.04) and high preoperative RDW levels in the 3rd quartile (>13.4% and ≤14.3%) and 4th quartile (>14.3%) were significantly associated with increased odds of 30-day mortality - (aOR 2.12, p = 0.02) and (aOR 2.85, p = 0.001) respectively, after adjusting for the effects of transfusion, surgical severity, priority of surgery, and comorbidities. Patients with high RDW, defined as >15.7% (90th centile), and preoperative anaemia have higher odds of 30-day mortality compared to patients with anaemia and normal RDW. Thus, preoperative RDW independently increases risk of 30-day postoperative mortality, and future risk stratification strategies should include RDW as a factor