Changing temporal trends in non-AIDS cancer mortality among people diagnosed with AIDS: San Francisco,California, 1996–2013

BackgroundAntiretroviral therapy (ART) has reduced AIDS-defining cancer (ADC) mortality, but its effect on non-AIDS-defining cancer (NADC) mortality is unclear. To help inform cancer prevention and screening, we evaluated trends in NADC mortality among people with AIDS (PWA) in the ART era.MethodsThis retrospective cohort study analyzed AIDS surveillance data, including causes of death from death certificates, for PWA in San Francisco who died in 1996–2013. Proportional mortality ratios (PMRs), and year, age, race, sex-adjusted standardized mortality ratios (SMRs) were calculated for 1996–1999, 2000–2005, and 2006–2013, corresponding to advances in ART.ResultsThe study included 5822 deceased PWA of whom 90% were male and 68% were aged 35–54 at time of death. Over time, the PMRs significantly decreased for ADCs (2.6%, 1.4%, 1.2%) and increased for NADCs (4.3%, 7.0%, 12.3%). For all years combined (1996–2013) and compared to the California population, significantly elevated SMRs were observed for these cancers: all NADCs combined (2.1), anal (58.4), Hodgkin lymphoma (10.5), liver (5.2), lung/larynx (3.0), rectal (5.2), and tongue (4.7). Over time, the SMRs for liver cancer (SMR 19.8, 11.2, 5.0) significantly decreased while the SMRs remained significantly elevated over population levels for anal (SMR 123, 48.2, 45.5), liver (SMR 19.8, 11.2, 5.0), and lung/larynx cancer (SMR 5.3, 4.7, 3.6).ConclusionA decline in ADC PMRs and increase in NADC PMRs represent a shift in the cancer burden, likely due to ART use. Moreover, given their elevated SMRs, anal, liver, and lung/larynx cancer remain targets for improved cancer prevention, screening, and treatment.     

Optimal Testing for Serial Correlation in a Large Number of Small Samples

In recent years, there has been an increased awareness of the potential one-sided nature of many testing problems in applied sciences. Usually, these testing problems can be reduced, either by conditioning on sufficient statistics or by invariant techniques. COX and SOLOMON (1988) considered testing the serial correlation coefficient of a stationary first order autoregressive process and concentrated on four independent samples, with each of size three. We outline a general method for testing the serial correlation coefficient, using locally best invariant, point optimal invariant and locally most mean powerful invariant test procedures. The first procedure optimizes power near the null hypothesis, the second optimizes it at a pre-determined point away from the null while the third optimizes the average curvature of the power hypersurface in the neighbourhood of the null hypothesis.     

Familial aggregation of human infection with Schistosoma japonicum in the Poyang Lake region, China

Despite the success of extensive control measures that have been implemented in China for over 50 years, the number of individuals infected with Schistosoma japonicum remains high in the existing endemic areas. A variance components analysis was undertaken to estimate the heritable and environmental components that contribute to S. japonicum infection in the Poyang Lake region of Jiangxi Province, PR China. The total target population was 3148 from four separate administrative villages. Two thousand seven hundred and five of these comprised 400 families ranging in size from 3 to 188. After adjustments were made for gender, water contact and past history of having had schistosomiasis, the heritable component was estimated to account for as much as 58% of the phenotype variation under the polygenic model. Household was not shown to be an important environmental factor. Incorporating village effects indicated that the results were valid for the total population. We conclude that genetic heritability in this region is high and plays an important role in determining risk of infection with S. japonicum.     

HIV/AIDS in Asia: The shape of epidemics and their molecular epidemiology

The Asia-Pacific region is a home to 60% of the population in the world and to approximately one quarter of people with HIV/AIDS. Close to a million of people has been infected and a half million people died of AIDS annually in Asia, becoming the second largest epicenter of global AIDS epidemic. Molecular epidemiology has been useful tool to track a course of HIV spread. In-depth knowledge from the studies on molecular epidemiology elucidates the dynamics of HIV spread and the interrelationship of epidemics in the different regions in Asia. Foundation items: Grant support from Ministry of Health, Labour and Welfare and Ministry of Education, Science and Technology in Japan; Japanese Foundation for AIDS Prevention.     

HIV/AIDS in Asia： The Shape of Epidemics and Their Molecular Epidemiology

The Asia-Pacific region is a home to 60% of the population in the world and to approximately one quarter of people with HIV/AIDS. Close to a million of people has been infected and a half million people died of AIDS annually in Asia,becoming the second largest epicenter of global AIDS epidemic. Molecular epidemiology has been useful tool to track a course of HIV spread. In-depth knowledge from the studies on molecular epidemiology elucidates the dynamics of HIV spread and the interrelationship of epidemics in the different regions in Asia.     

Numerical comparison between powers of maximum likelihood and analysis of variance methods for QTL detection in progeny test designs: the case of monogenic inheritance

Simulations are used to compare four statistics for the detection of a quantitative trait locus (QTL) in daughter and grand-daughter designs as defined by Soller and Genizi (1978) and Weller et al. (1990): (1) the Fisher test of a linear model including a marker effect within sire or grand-sire effect; (2) the likelihood ratio test of a segregation analysis without the information given by the marker; (3) the likelihood ratio test of a segregation analysis considering the information from the marker; and (4) the lod score which is the likelihood ratio test of absence of linkage between the marker and the QTL. In all cases the two segregation analyses are more powerful for QTL detection than are either the linear method or the lod score. The differences in power are generally limited but may be significant (in a ratio of 1 to 3 or 4) when the QTL has a small effect (0.2 standard deviations) and is not closely linked to the marker (recombination rate of 20% or more).     

An Evaluation of Different Methods in Epidemiologic Studies of Radiation Risks

The probability of detecting possible late effects of ionizing radiation in human populations depends on the size of exposure in the study population and on the epidemiologic evaluation method used. This is not only due to the mathematical or statistical properties of the method, but also to the choice of the control population, which may be either external (usually large) or internal (usually not so large). Moreover, the use of a large external control population often results in an increasing influence of selection factors expressing themselves e.g. through the ‘healthy worker’ effect. In this paper three different methods usually employed in follow-up studies are reviewed: the calculation of Standardized Mortality Ratios (SMR), a contingency table analysis based on Person-Years (PY) and the comparison of Cumulative Mean Doses (CMD) within different subcohorts. The methods are illustrated with a simple radiation risk model; nevertheless, most of the conclusions apply to non-radiation risk studies as well. The CMD-method is shown to be heavily selection sensitive.     

渐近混合群体的混合连锁不平衡及其遗传连锁推断

在渐近混合模型中,混合现象发生在每一世代,通过对其混合连锁不平衡的理论分析,发现混合连锁不平衡与两个子群体间的基因频率差成正比。基于这一点,构造了一个对重组率严格单调的函数（△ker=△／（p1-p2）,其中△代表连锁不平衡）,进而据此推断标记基因座与疾病基因座的遗传连锁。应用人类基因组上不连锁的标记基因提供的连锁不平衡信息,基于病人组数据构造了一个准似然比统计量。模拟结果显示,此检验可用于精确的基因定位。文章亦讨论了参数对检验的影响。     

The Admixture Linkage Disequilibrium and Genetic Linkage Inference on the Gradual Admixture Population

Through the theoretical analysis of the admixture linkage disequilibrium (ALD) in the gradual admixture (GA) model, in which admixture occurs in every generation, the ALD is found to be proportional to the difference in marker allele frequencies, p₁-p₂, between two subpopulations. Based on this property, we can employ a strict monotonic function (Δ_ker=Δ/(p₁-p₂), where Δ denotes the linkage disequilibrium (LD)) of the recombination fraction between the marker locus and the disease locus to infer the true genetic linkage. We construct a quasi likelihood ratio test (LRT) for the case-only data utilizing the information of unlinked markers in the human genome. The simulation results show that our tests can be used to fine map a disease locus. The effects of parameter values in the ALD mapping are also discussed.     

Multiple-population versus hierarchical conifer breeding programs: a comparison of genetic diversity levels

Advanced-generation domestication programs for forest-tree species has raised some concerns about the maintenance of genetic diversity in forest-tree breeding programs. Genetic diversity in natural stands was compared with two genetic conservation options for a third-generation elite Pinus taeda breeding population. The breeding population was subdivided either on the basis of geographic origin and selection goals (multiple-population or MPBS option) or stratified according to genetic value (hierarchical or HOPE option). Most allelic diversity in the natural stands of loblolly pine is present in the domesticated breeding populations. This was true at the aggregate level for both multiple-population (MPBS) and the hierarchical (HOPE) populations. Individual subpopulations within each option had less genetic diversity but it did not decline as generations of improvement increased. Genetic differentiation within the subdivided breeding populations ranged from 1 to 5%, genetic variability is within each subpopulation rather than among subpopulations for both MPBS (>95%) and the HOPE approaches (>98%). Nei's G_st estimates for amongpopulation differentiation were biased upwards relative to estimates of from Weir and Cockerham (1984).     

雨生红球藻中IPP异构酶基因的系统发育分析

通过系统进化树的构建对IPP异构酶的系统发育进行分析研究。结果表明,不同来源的IPP异构酶基因均是单系分支,并且各个分支有着不同进化模式;似然比分析结果发现,绿藻来源的IPP异构酶有9．8％的氨基酸位点经受了正选择的压力,其基因的进化模式不同于高等植物和细菌中的IPP异构酶基因。     

Aggregation Properties of the Small Nuclear Ribonucleoprotein U1-70K in Alzheimer Disease

Recent evidence indicates that U1-70K and other U1 small nuclear ribonucleoproteins are Sarkosyl-insoluble and associate with Tau neurofibrillary tangles selectively in Alzheimer disease (AD). Currently, the mechanisms underlying the conversion of soluble nuclear U1 small nuclear ribonucleoproteins into insoluble cytoplasmic aggregates remain elusive. Based on the biochemical and subcellular distribution properties of U1-70K in AD, we hypothesized that aggregated U1-70K itself or other biopolymers (e.g. proteins or nucleic acids) interact with and sequester natively folded soluble U1-70K into insoluble aggregates. Here, we demonstrate that total homogenates from AD brain induce soluble U1-70K from control brain or recombinant U1-70K to become Sarkosyl-insoluble. This effect was not dependent on RNA and did not correlate with detergent-insoluble Tau levels as AD homogenates with reduced levels of these components were still capable of inducing U1-70K aggregation. In contrast, proteinase K-treated AD homogenates and Sarkosyl-soluble AD fractions were unable to induce U1-70K aggregation, indicating that aggregated proteins in AD brain are responsible for inducing soluble U1-70K aggregation. It was determined that the C terminus of U1-70K, which harbors two disordered low complexity (LC) domains, is necessary for U1-70K aggregation. Moreover, both LC1 and LC2 domains were sufficient for aggregation. Finally, protein cross-linking and mass spectrometry studies demonstrated that a U1-70K fragment harboring the LC1 domain directly interacts with aggregated U1-70K in AD brain. Our results support a hypothesis that aberrant forms of U1-70K in AD can directly sequester soluble forms of U1-70K into insoluble aggregates.     

Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins

Aha1 (activator of Hsp90 ATPase) stimulates the ATPase activity of the molecular chaperone Hsp90 to accelerate the conformational cycle during which client proteins attain their final shape. Thereby, Aha1 promotes effective folding of Hsp90-dependent clients such as steroid receptors and many kinases involved in cellular signaling. In our current study, we find that Aha1 plays a novel, additional role beyond regulating the Hsp90 ATP hydrolysis rate. We propose a new concept suggesting that Aha1 acts as an autonomous chaperone and associates with stress-denatured proteins to prevent them from aggregation similar to the chaperonin GroEL. Our study reveals that an N-terminal sequence of 22 amino acids, present in human but absent from yeast Aha1, is critical for this capability. However, in lieu of fostering their refolding, Aha1 allows ubiquitination of bound clients by the E3 ubiquitin ligase CHIP. Accordingly, Aha1 may promote disposal of folding defective proteins by the cellular protein quality control.     

A comparison of non-iterative and iterative estimators of heterogeneity variance for the standardized mortality ratio

This paper continues work presented in B?hning et al. (2002b, Annals of the Institute of Statistical Mathematics 54, 827-839, henceforth BMSRB) where a class of non-iterative estimators of the variance of the heterogeneity distribution for the standardized mortality ratio was discussed. Here, these estimators are further investigated by means of a simulation study. In addition, iterative estimators including the Clayton-Kaldor procedure as well as the pseudo-maximum-likelihood (PML) approach are added in the comparison. Among all candidates, the PML estimator often has the smallest mean square error, followed by the non-iterative estimator where the weights are proportional to the external expected counts. This confirms the theoretical result in BMSRB in which an asymptotic efficiency could be proved for this estimator (in the class of non-iterative estimators considered). Surprisingly, the Clayton-Kaldor iterative estimator (often recommended and used by practitioners) performed poorly with respect to the MSE. Given the widespread use of these estimators in disease mapping, medical surveillance, meta-analysis and other areas of public health, the results of this study might be of considerable interest.     

Estimation of the contribution of quantitative trait loci (QTL) to the variance of a quantitative trait by means of genetic markers

The estimation of the contribution of an individual quantitative trait locus (QTL) to the variance of a quantitative trait is considered in the framework of an analysis of variance (ANOVA). ANOVA mean squares expectations which are appropriate to the specific case of QTL mapping experiments are derived. These expectations allow the specificities associated with the limited number of genotypes at a given locus to be taken into account. Discrepancies with classical expectations are particularly important for two-class experiments (backcross, recombinant inbred lines, doubled haploid populations) and F₂ populations. The result allows us firstly to reconsider the power of experiments (i.e. the probability of detecting a QTL with a given contribution to the variance of the trait). It illustrates that the use of classical formulae for mean squares expectations leads to a strong underestimation of the power of the experiments. Secondly, from the observed mean squares it is possible to estimate directly the variance associated with a locus and the fraction of the total variance associated to this locus (r _l ² ). When compared to other methods, the values estimated using this method are unbiased. Considering unbiased estimators increases in importance when (1) the experimental size is limited; (2) the number of genotypes at the locus of interest is large; and (3) the fraction of the variation associated with this locus is small. Finally, specific mean squares expectations allows us to propose a simple analytical method by which to estimate the confidence interval of r _l ² . This point is particularly important since results indicate that 95% confidence intervals for r _l ² can be rather wide:2–23% for a 10% estimate and 8–34% for a 20% estimate if 100 individuals are considered.     

Cooperation: The roles of interpersonal value and gratitude

Here we examine the roles of interpersonal valuation and gratitude in the formation of cooperative relationships. Building on prior work, we draw on the concept of a welfare tradeoff ratio (WTR), an internally computed index of the extent to which one person values another person's welfare relative to his or her own. We test several predictions regarding the effects of benefit delivery on changes in WTR, gratitude, and subsequent cooperation. We show that benefit delivery by a stranger: (i) raises the beneficiary's valuation of the stranger's welfare, (ii) predicts downstream cooperative behavior by the beneficiary toward the stranger, and (iii) is coincident with beneficiaries' expressions of gratitude. We find evidence that cooperation and gratitude, while both sparked via benefit delivery and both underpinned by estimates of welfare valuation, are nevertheless produced in parallel via different paths. Specifically, the updated magnitude—not the initial magnitude or degree of change—of a beneficiary's WTR toward a stranger predicts the beneficiary's downstream cooperative behavior. By contrast, the extent to which the beneficiary's WTR positively changes—and not the initial or updated WTR magnitude—predicts gratitude production, a feature proposed to reinforce the benefactor's actions and foreshadow future cooperative intent on the part of the beneficiary. Taken together, our findings point to the possibility that cooperative behavior might operate via internal estimates of welfare valuation, and that gratitude signals benefit reception and the intent to engage in a cooperative relationship.