Serial struggles : English Catholics and their periodicals,1648-1844

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Interpreting Posterior Relative Risk Estimates in Disease-Mapping Studies

There is currently much interest in conducting spatial analyses of health outcomes at the small-area scale. This requires sophisticated statistical techniques, usually involving Bayesian models, to smooth the underlying risk estimates because the data are typically sparse. However, questions have been raised about the performance of these models for recovering the “true” risk surface, about the influence of the prior structure specified, and about the amount of smoothing of the risks that is actually performed. We describe a comprehensive simulation study designed to address these questions. Our results show that Bayesian disease-mapping models are essentially conservative, with high specificity even in situations with very sparse data but low sensitivity if the raised-risk areas have only a moderate (< 2-fold) excess or are not based on substantial expected counts (> 50 per area). Semiparametric spatial mixture models typically produce less smoothing than their conditional autoregressive counterpart when there is sufficient information in the data (moderate-size expected count and/or high true excess risk). Sensitivity may be improved by exploiting the whole posterior distribution to try to detect true raised-risk areas rather than just reporting and mapping the mean posterior relative risk. For the widely used conditional autoregressive model, we show that a decision rule based on computing the probability that the relative risk is above 1 with a cutoff between 70 and 80% gives a specific rule with reasonable sensitivity for a range of scenarios having moderate expected counts (~ 20) and excess risks (~1.5- to 2-fold). Larger (3-fold) excess risks are detected almost certainly using this rule, even when based on small expected counts, although the mean of the posterior distribution is typically smoothed to about half the true value

Individual differences in search and monitoring for color targets in dynamic visual displays

Many jobs now involve the monitoring visual representations of data that change over time. Monitoring dynamically changing displays for the onset of targets can be done in two ways: detecting targets directly post their onset or predicting their onset from the prior state of distractors. In the present study, participants? eye movements were measured as they monitored arrays of 108 colored squares whose colors changed systematically over time. Across three experiments, the data show that participants detected the onset of targets both directly and predictively. Experiments 1 and 2 showed that predictive detection was only possible when supported by sequential color changes that followed a scale ordered in color space. Experiment 3 included measures of individual differences in working memory capacity (WMC) and anxious affect and a manipulation of target prevalence in the search task. It found that predictive monitoring for targets, and decisions about target onsets, were influenced by interactions between individual differences in verbal and spatial WMC and intolerance of uncertainty, a characteristic that reflects worry about uncertain future events. The results have implications for the selection of individuals tasked with monitoring dynamic visual displays for target onsets

Nutritional status and dental caries in a large sample of 4- and 5-year-old South African children

Background. Evidence from studies involving small samples of children in Africa, India and South America suggests a higher dental caries rate in malnourished children. A comparison was done to evaluate wasting and stunting and their association with dental caries in four samples of South African children.Design. Cross-sectional study based on random sampling of birth records of two age bands.Methods. A total of 2 728 4- and 5-year-old South African children from one rural community and three urban. communities were examined for nutritional status and dental caries.Results. In the total sample prevalences of wasting were mild (28%), moderate (4%) and severe (2%). For stunting the prevalences were mild (13%), moderate (3%) and severe (1%). For both conditions rural children showed higher proportions than the other groups. Statistical analysis showed statistically significant differences for wasting and stunting between the study groups. No significant association was found between the prevalence of caries and stunting or wasting, but an association was noted between wasting and decayed, missing and filled (drnf) surfaces (P = 0.003).Conclusions. In the series of children studied, nutritional status was not found to be clinically relevant to dental caries prevalence and experience

Disarmed anthrax toxin delivers antisense oligonucleotides and siRNA with high efficiency and low toxicity

Inefficient cytosolic delivery and vector toxicity contribute to the limited use of antisense oligonucleotides (ASOs) and siRNA as therapeutics. As anthrax toxin (Atx) accesses the cytosol, the purpose of this study was to evaluate the potential of disarmed Atx to deliver either ASOs or siRNA. We hypothesized that this delivery strategy would facilitate improved transfection efficiency while eliminating the toxicity seen for many vectors due to membrane destabilization. Atx complex formation with ASOs or siRNA was achieved via the in-frame fusion of either Saccharomyces cerevisiae GAL4 or Homo sapien sapien PKR (respectively) to a truncation of Atx lethal factor (LFn), which were used with Atx protective antigen (PA). Western immunoblotting confirmed the production of: LFN-GAL4, LFn-PKR and PA which were detected at ~ 45.9 kDa, ~ 37 kDa, and ~ 83 kDa respectively and small angle neutron scattering confirmed the ability of PA to form an annular structure with a radius of gyration of 7.0 ± 1.0 nm when placed in serum. In order to form a complex with LFn-GAL4, ASOs were engineered to contain a double-stranded region, and a cell free in vitro translation assay demonstrated that no loss of antisense activity above 30 pmol ASO was evident. The in vitro toxicity of both PA:LFn-GAL4:ASO and PA:LFn-PKR:siRNA complexes was low (IC50 > 100 μg/mL in HeLa and Vero cells) and subcellular fractionation in conjunction with microscopy confirmed the detection of LFn-GAL4 or LFn-PKR in the cytosol. Syntaxin5 (Synt5) was used as a model target gene to determine pharmacological activity. The PA:LFn-GAL4:ASO complexes had transfection efficiency approximately equivalent to Nucleofection® over a variety of ASO concentrations (24 h post-transfection) and during a 72 h time course. In HeLa cells, at 200 pmol ASO (with PA:LFN-GAL4), 5.4 ± 2.0% Synt5 expression was evident relative to an untreated control after 24 h. Using 200 pmol ASOs, Nucleofection® reduced Synt5 expression to 8.1 ± 2.1% after 24 h. PA:LFn-GAL4:ASO transfection of non- or terminally-differentiated THP-1 cells and Vero cells resulted in 35.2 ± 19.1%, 36.4 ± 1.8% and 22.9 ± 6.9% (respectively) Synt5 expression after treatment with 200 pmol of ASO and demonstrated versatility. Nucleofection® with Stealth RNAi™ siRNA reduced HeLa Synt5 levels to 4.6 ± 6.1% whereas treatment with the PA:LFn-PKR:siRNA resulted in 8.5 ± 3.4% Synt5 expression after 24 h (HeLa cells). These studies report for the first time an ASO and RNAi delivery system based upon protein toxin architecture that is devoid of polycations. This system may utilize regulated membrane back-fusion for the cytosolic delivery of ASOs and siRNA, which would account for the lack of toxicity observed. High delivery efficiency suggests further in vivo evaluation is warranted

An in vitro evaluation of epigallocatechin gallate (eGCG) as a biocompatible inhibitor of ricin toxin

The catechin, epigallocatechin gallate (eGCG), found in green tea, has inhibitory activity against a number of protein toxins and was investigated in relation to its impact upon ricin toxin (RT) in vitro. The IC50 for RT was 0.08 ± 0.004 ng/mL whereas the IC50 for RT + 100 μM eGCG was 3.02 ± 0.572 ng/mL, indicating that eGCG mediated a significant (p < 0.0001) reduction in ricin toxicity. This experiment was repeated in the human macrophage cell line THP-1 and IC50 values were obtained for RT (0.54 ± 0.024 ng/mL) and RT + 100 μM eGCG (0.68 ± 0.235 ng/mL) again using 100 μM eGCG and was significant (p = 0.0013). The documented reduction in ricin toxicity mediated by eGCG was found to be eGCG concentration dependent, with 80 and 100 μg/mL (i.e. 178 and 223 μM respectively) of eGCG mediating a significant (p = 0.0472 and 0.0232) reduction in ricin toxicity at 20 and 4 ng/ml of RT in Vero and THP-1 cells (respectively). When viability was measured in THP-1 cells by propidium iodide exclusion (as opposed to the MTT assays used previously) 10 ng/mL and 5 ng/mL of RT was used. The addition of 1000 μM and 100 μM eGCG mediated a significant (p = 0.0015 and < 0.0001 respectively) reduction in ricin toxicity relative to an identical concentration of ricin with 1 μg eGCG. Further, eGCG (100 μM) was found to reduce the binding of RT B chain to lactose-conjugated Sepharose as well as significantly (p = 0.0039) reduce the uptake of RT B chain in Vero cells. This data suggests that eGCG may provide a starting point to refine biocompatible substances that can reduce the lethality of ricin

Effect on life expectancy of temporal sequence in a multimorbidity cluster of psychosis, diabetes, and congestive heart failure among 1·7 million individuals in Wales with 20-year follow-up: a retrospective cohort study using linked data

BACKGROUND: To inform targeted public health strategies, it is crucial to understand how coexisting diseases develop over time and their associated impacts on patient outcomes and health-care resources. This study aimed to examine how psychosis, diabetes, and congestive heart failure, in a cluster of physical-mental health multimorbidity, develop and coexist over time, and to assess the associated effects of different temporal sequences of these diseases on life expectancy in Wales. METHODS: In this retrospective cohort study, we used population-scale, individual-level, anonymised, linked, demographic, administrative, and electronic health record data from the Wales Multimorbidity e-Cohort. We included data on all individuals aged 25 years and older who were living in Wales on Jan 1, 2000 (the start of follow-up), with follow-up continuing until Dec 31, 2019, first break in Welsh residency, or death. Multistate models were applied to these data to model trajectories of disease in multimorbidity and their associated effect on all-cause mortality, accounting for competing risks. Life expectancy was calculated as the restricted mean survival time (bound by the maximum follow-up of 20 years) for each of the transitions from the health states to death. Cox regression models were used to estimate baseline hazards for transitions between health states, adjusted for sex, age, and area-level deprivation (Welsh Index of Multiple Deprivation [WIMD] quintile). FINDINGS: Our analyses included data for 1 675 585 individuals (811 393 [48·4%] men and 864 192 [51·6%] women) with a median age of 51·0 years (IQR 37·0-65·0) at cohort entry. The order of disease acquisition in cases of multimorbidity had an important and complex association with patient life expectancy. Individuals who developed diabetes, psychosis, and congestive heart failure, in that order (DPC), had reduced life expectancy compared with people who developed the same three conditions in a different order: for a 50-year-old man in the third quintile of the WIMD (on which we based our main analyses to allow comparability), DPC was associated with a loss in life expectancy of 13·23 years (SD 0·80) compared with the general otherwise healthy or otherwise diseased population. Congestive heart failure as a single condition was associated with mean a loss in life expectancy of 12·38 years (0·00), and with a loss of 12·95 years (0·06) when preceded by psychosis and 13·45 years (0·13) when followed by psychosis. Findings were robust in people of older ages, more deprived populations, and women, except that the trajectory of psychosis, congestive heart failure, and diabetes was associated with higher mortality in women than men. Within 5 years of an initial diagnosis of diabetes, the risk of developing psychosis or congestive heart failure, or both, was increased. INTERPRETATION: The order in which individuals develop psychosis, diabetes, and congestive heart failure as combinations of conditions can substantially affect life expectancy. Multistate models offer a flexible framework to assess temporal sequences of diseases and allow identification of periods of increased risk of developing subsequent conditions and death. FUNDING: Health Data Research UK