Preventable cancer mortality in American Indian and Alaska Native women.

This report describes a series of six studies on cancer in American Indian and Alaska Native (AI/AN) women, with a particular emphasis on cancer of the breast and cervix. Data from the Indian Health Service (IHS) inpatient data system was used to generate estimates of incidence of cancer among AI/AN populations. Additionally, breast cancer rates among Indian women in Arizona and New Mexico were compiled from extensive chart review of the New Mexico Tumor Registry and the IHS Inpatient Data System. Study of the performance of the health care system for cancer screening in women suggest that the major deficiency lies not in a failure to bring women in for screening, but rather to complete the screening after contact has been made and the need for screening recognized. The studies indicate that cancer is generally diagnosed in American Indian women at a more advanced stage and survival experience of Indian cancer patients is worse than non-Indian, even when corrected for later stage at diagnosis. Several of the studies suggest that failure to diagnose cancer in its very early stages appears to be in large part dependent on patient behavior. An alarming number of women do not keep follow-up appointments, even after multiple referrals and rescheduling of appointments. These findings suggest the need for intervention strategies that encourage women to become knowledgeable about cancer and to accept responsibility for their screening. The studies suggest that the relative difficulty in improving screening rates are traced to an inadequate understanding of cancer and its prevention on the part of women in the community

Studies in Ambulatory Care Quality Assessment in the Indian Health Service

This report describes a method designed to assess the quality of ambulatory health care in the Indian Health Service. This evaluation approaches the issue of quality assurance for ambulatory care through three basic performance criteria: 1) the method must be easily and economically incorporated into the existing system; 2) the method must identify areas of deficiency in health care and suggest adaptive programs to correct deficiencies; and 3) the method must view health care from the community perspective and examine the quality of the care actually received.This study design was developed around six methodological design questions: 1) what mode of health care delivery is assessed; 2) what aspect of quality is measured; 3) what is the content of the evaluation; 4) how is quality assessed; 5) from what perspective are the measurements taken; and 6) how are the results analyzed? The results of the above design decisions are then used to develop criteria-based indicators and instruments. The project product is a set of flow charts or process maps and tables which outline in detail, the performance and process criteria, and forms to be used to connect data and index the progress and effectiveness of actual patient status and health care performance. The final stage in the process is to propose a design for field testing the established methodology. The evaluation instrument was successfully completed, and implemented at the field test study sites.For the purpose of improving the pilot study and subsequent evaluations, the designers of this methodology strongly suggest that: 1) audit specific data should include all usual patient status data, complete patient history data, including negative as well as positive progress, and educational counseling plans and outcomes; 2) validity of proposed criteria ought to be supported by controlled clinical studies; and 3) only those elements of care which can actually be changed should be subjected to compliance with performance criteria

Explicit de Sitter Flux Vacua for Global String Models with Chiral Matter

We address the open question of performing an explicit stabilisation of all closed string moduli (including dilaton, complex structure and Kaehler moduli) in fluxed type IIB Calabi-Yau compactifications with chiral matter. Using toric geometry we construct Calabi-Yau manifolds with del Pezzo singularities. D-branes located at such singularities can support the Standard Model gauge group and matter content. In order to control complex structure moduli stabilisation we consider Calabi-Yau manifolds which exhibit a discrete symmetry that reduces the effective number of complex structure moduli. We calculate the corresponding periods in the symplectic basis of invariant three-cycles and find explicit flux vacua for concrete examples. We compute the values of the flux superpotential and the string coupling at these vacua. Starting from these explicit complex structure solutions, we obtain AdS and dS minima where the Kaehler moduli are stabilised by a mixture of D-terms, non-perturbative and perturbative alpha'-corrections as in the LARGE Volume Scenario. In the considered example the visible sector lives at a dP_6 singularity which can be higgsed to the phenomenologically interesting class of models at the dP_3 singularity.Comment: 49 pages, 5 figures; v2: references adde

Discontinuation of a randomised controlled trial in general practice due to unsuccessful patient recruitment.

BACKGROUND: A randomised controlled trial (RCT) in general practice, recruiting incident patients with (sub)acute sciatica, was discontinued because of insufficient recruitment. AIM: To describe factors that influenced the recruitment process and ultimately led to discontinuation of this trial, and to enable others to learn from this experience. DESIGN & SETTING: A pragmatic RCT was designed to compare two pain medication prescription strategies for treatment of (sub)acute sciatica in general practice. After 1 year of patient recruitment, the trial was prematurely terminated. METHOD: To analyse the underperforming recruitment, patient information systems of 20 general practices were screened twice a month to search for eligible patients and identify reasons for non-eligibility. Secondly, after study termination, an open question was distributed to the participating GPs for their views on the recruitment process. RESULTS: A total of 116 GPs from 37 general practices collaborated in the trial. Only eight of 234 patients were included after 12 months. The 22 GPs who offered their opinion on the main reasons for unsuccessful recruitment considered that these were the low incidence rate and strict eligibility criteria, a strong patient and/or GP preference, and time constraints. CONCLUSION: For this RCT, multiple factors were related to recruitment problems but it remains unknown which determinants prevailed. As the research question is unanswered but remains relevant, it is recommended that GPs' daily practice is taken into account when designing an RCT, a pilot study should be performed for feasibility of recruitment, and GP assistants should be involved at an early stage

Effects of food-borne nanomaterials on gastrointestinal tissues and microbiota

Ingestion of engineered nanomaterials is inevitable due to their addition to food and prevalence in food packaging and domestic products such as toothpaste and sun cream. In the absence of robust dosimetry and particokinetic data, it is currently challenging to accurately assess the potential toxicity of food-borne nanomaterials. Herein, we review current understanding of gastrointestinal uptake mechanisms, consider some data on the potential for toxicity of the most commonly encountered classes of food-borne nanomaterials (including TiO2 , SiO2 , ZnO, and Ag nanoparticles), and discuss the potential impact of the luminal environment on nanoparticle properties and toxicity. Much of our current understanding of gastrointestinal nanotoxicology is derived from increasingly sophisticated epithelial models that augment in vivo studies. In addition to considering the direct effects of food-borne nanomaterials on gastrointestinal tissues, including the potential role of chronic nanoparticle exposure in development of inflammatory diseases, we also discuss the potential for food-borne nanomaterials to disturb the normal balance of microbiota within the gastrointestinal tract. The latter possibility warrants close attention given the increasing awareness of the critical role of microbiota in human health and the known impact of some food-borne nanomaterials on bacterial viability. For further resources related to this article, please visit the WIREs website.</p

A Calculation of the Full Neutrino Phase Space in Cold+Hot Dark Matter Models

This paper presents a general-relativistic N-body technique for evolving the phase space distribution of massive neutrinos in linear perturbation theory. The method provides a much more accurate sampling of the neutrino phase space for the HDM initial conditions of N-body simulations in a cold+hot dark matter universe than previous work. Instead of directly sampling the phase space at the end of the linear era, we first compute the evolution of the metric perturbations by numerically integrating the coupled, linearized Einstein, Boltzmann, and fluid equations for all particle species. We then sample the phase space shortly after neutrino decoupling at redshift z=10^9 when the distribution is Fermi-Dirac. To follow the trajectory of each neutrino, we subsequently integrate the geodesic equations for each neutrino in the perturbed background spacetime from z=10^9 to z=13.55, using the linearized metric found in the previous calculation to eliminate discreteness noise. The positions and momenta resulting from this integration represent a fair sample of the full neutrino phase space and can be used as HDM initial conditions for N-body simulations of nonlinear structure evolution in this model. A total of 21 million neutrino particles are used in a 100 Mpc box, with Omega_cdm=0.65, Omega_hdm=0.30, Omega_baryon=0.05, and Hubble constant H_0=50. We find that correlations develop in the neutrino densities and momenta which are absent when only the zeroth-order Fermi-Dirac distribution is considered.Comment: 20 pages, AAS LaTeX v3.0, figures and/or postscript available by anonymous ftp to arcturus.mit.edu, MIT CSR-93-1

A random cell motility gradient downstream of FGF controls elongation of amniote embryos

Vertebrate embryos are characterized by an elongated antero-posterior (AP) body axis, which forms by progressive cell deposition from a posterior growth zone in the embryo. Here, we used tissue ablation in the chicken embryo to demonstrate that the caudal presomitic mesoderm (PSM) has a key role in axis elongation. Using time-lapse microscopy, we analysed the movements of fluorescently labelled cells in the PSM during embryo elongation, which revealed a clear posterior-to-anterior gradient of cell motility and directionality in the PSM. We tracked the movement of the PSM extracellular matrix in parallel with the labelled cells and subtracted the extracellular matrix movement from the global motion of cells. After subtraction, cell motility remained graded but lacked directionality, indicating that the posterior cell movements associated with axis elongation in the PSM are not intrinsic but reflect tissue deformation. The gradient of cell motion along the PSM parallels the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK) gradient1, which has been implicated in the control of cell motility in this tissue2. Both FGF signalling gain- and loss-of-function experiments lead to disruption of the motility gradient and a slowing down of axis elongation. Furthermore, embryos treated with cell movement inhibitors (blebbistatin or RhoK inhibitor), but not cell cycle inhibitors, show a slower axis elongation rate. We propose that the gradient of random cell motility downstream of FGF signalling in the PSM controls posterior elongation in the amniote embryo. Our data indicate that tissue elongation is an emergent property that arises from the collective regulation of graded, random cell motion rather than by the regulation of directionality of individual cellular movements

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy.

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity

Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy

Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure and a poor prognosis from late adolescence. It can be diagnosed in whole heart specimens, but rarely in right ventricular biopsy specimens, by PLN immunohistochemistry showing PLN-containing aggregates concentrated in cardiomyocytes in dense perinuclear aggresomes. The purpose of this study was to determine whether PLN immunohistochemistry can be used to diagnose PLN p.Arg14del cardiomyopathy using apical left ventricular myocardial specimens harvested during left ventricular assist device (LVAD) implantation. At that stage, a genetic diagnosis, which may guide treatment and referral of family members for further investigation, is frequently not established yet. Included were myocardial specimens from 30 diverse genetic cardiomyopathy cases with known variants (9 carriers of the pathogenic PLN p.Arg14del variant, 18 cases with other pathogenic or likely pathogenic variants in cardiomyopathy-related genes, and 3 with only variants of unknown significance). Immunohistochemical analysis revealed typical dense perinuclear globular PLN-positive aggregates, representing aggresomes, in all nine PLN p.Arg14del cases. In 20 non-PLN cases, PLN-staining was absent. In one non-PLN case, one of the two independent observers misinterpreted PLN staining of heavily wrinkled nuclear membranes of cardiomyocytes as perinuclear PLN aggregates. In this genetic cardiomyopathy cohort, PLN Immunohistochemical analysis in LVAD biopsies was found to be a highly sensitive (100%) and specific (95%) method for demonstration of PLN protein aggregates in PLN p.Arg14del cardiomyopathy. In clinical practice, PLN immunohistochemical analysis of LVAD specimens can be of incremental value in the diagnostic workup of this cardiomyopathy, even more so if genetic analysis is not readily available