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Methyl mercury (MeHg) is neurotoxic and all fish contain at least trace amounts. Consequently, prenatal or fetal exposure occurs when pregnant women consume fish and children are exposed postnatally when they breastfeed or consume fish. However, the level of exposure at which toxicity occurs is presently unknown. Since behavioural endpoints can be sensitive indicators of toxic exposure, we administered the Child Behaviour Checklist (CBCL) to measure behaviour as part of a prospective, longitudinal, double blind study (n = 779) of prenatal MeHg exposure, the Seychelles Child Development Study (SCDS). The CBCL Total T score was a primary endpoint at 66 and 107 month evaluations of the cohort and showed no association with prenatal or postnatal MeHg exposure. This paper reports the results of a secondary analysis of the CBCL subscales to see if specific aspects of behaviour might show associations. The SCDS main cohort was enrolled in 1989-90 and evaluated on five occasions through 107 months of age. The child's primary caregiver completed the CBCL at the 107 month evaluation. Prenatal exposure was determined by measuring total mercury (THg) in maternal hair growing during pregnancy and recent postnatal exposure by analysing the child's hair taken at the 107 month evaluation. Analysis included linear and nonlinear multiple regression models. For prenatal MeHg exposure, the Social Problems subscale was significantly associated and the Somatic Complaints subscale was marginally associated. Both were beneficial associations. For postnatal exposure the Thought Problems subscale was associated in an adverse direction. This secondary analysis identified a small number of subtle beneficial and adverse associations with prenatal and postnatal MeHg exposure for specific CBCL subscales. These analyses provide no evidence for an adverse effect of prenatal exposure. The adverse postnatal association is difficult to interpret because we measured only recent (about one month) exposure and no adjustment was made for the multiplicity of endpoints.

Objective: Falun Gong (FLG) is a practice of mind and body focusing on moral character improvement that includes meditative exercises. In this study, we explored perceived health status, healthcare resource utilization, and related factors among Taiwanese FLG practitioners, compared to themselves before practicing FLG, and also to the general Taiwanese norm, as reported by the 2001 National Health Interview Survey (NHIS). Methods: This cross-sectional study was based on a voluntary, paper-based survey conducted from October 2002 to February 2003 using the same Taiwanese SF-36 instrument employed by the NHIS. Primary outcomes included 8 SF-36 domain scores and the number of outpatient visits. One-sample t-tests, oneway ANOVA, and multivariate linear regression analyses were used. Results: The response rate was 75.6% (1210/1600). Compared to the norm, the study cohort had significantly higher scores in 6 of 8 SF-36 domains across sex and age (p < .05). Among those with chronic diseases, 70% to 89% reported that their conditions were improved or cured. Additionally, 74.2% and 79.2% participants stopped drinking alcohol and quit smoking; 62.7% reported decreased outpatient visits (mean before = 11.96; mean after = 5.87; norm = 14.4). Conclusions: In this cohort, FLG participants had higher perceived health scores than the population norm and reduced outpatient visits than before practice.

Nonlinear correlation exists in many types of biomedical data. Several types of pairwise gene expression in humans and other organisms show nonlinear correlation across time, e.g., genes involved in human T helper (Th17) cells differentiation, which motivated this study. The proposed procedure, called Kernelized correlation (Kc), first transforms nonlinear data on the plane via a function (kernel, usually nonlinear) to a high-dimensional (Hilbert) space. Next, we plug the transformed data into a classical correlation coefficient, e.g., Pearson’s correlation coefficient (r), to yield a nonlinear correlation measure. The algorithm to compute Kc is developed and the R code is provided online. In three simulated nonlinear cases, when noise in data is moderate, Kc with the RBF kernel (Kc-RBF) outperforms Pearson’s r and the well-known distance correlation (dCor). However, when noise in data is low, Pearson’s r and dCor perform slightly better than (equivalently to) Kc-RBF in Case 1 and 3 (in Case 2); Kendall’s tau performs worse than the aforementioned measures in all cases. In Application 1 to discover genes involved in the early Th17 cell differentiation, Kc is shown to detect the nonlinear correlations of four genes with IL17A (a known marker gene), while dCor detects nonlinear correlations of two pairs, and DESeq fails in all these pairs. Next, Kc outperforms Pearson’s and dCor, in estimating the nonlinear correlation of negatively correlated gene pairs in yeast cell cycle regulation. In conclusion, Kc is a simple and competent procedure to measure pairwise nonlinear correlations.

Smooth backfitting has been shown to have better theoretical properties than classical backfitting for fitting additive models based on local linear regression. In this article, we show that the sm...

The Seychelles Child Development Study is a longitudinal cohort study following a group of 779 children exposed prenatally to methyl mercury (MeHg) through a maternal diet high in fish. The cohort has been examined six times beginning in infancy with no consistent evidence of adverse effects. In fact, their performance resembles what would be expected from normal children of comparable ages growing up in western cultures. During a neurodevelopment assessment at 66 months, the children were tested for scholastic achievement using the Woodcock Johnson Tests of Achievement. Their reading scores were depressed relative to US norms while arithmetic scores were within normal limits. This disparity was not evident at 107 months; in fact, reading achievement scores far exceeded expected performance relative to US norms, with over 75% of the cohort obtaining scores at or above the 90th percentile. This study reports a secondary analysis of the scholastic achievement data to test the hypothesis that the results obtained in the primary analysis were probably due to the onset of the primary school curriculum between the first and second testing, and not to inherent cognitive deficits among the children at 66 months. The results suggest that a combination of reading instruction and characteristically consistent letter-sound relationships in Creole, the language spoken at home by the majority of Seychellois families, probably accounted for the high achievement scores at 107 months.

Motivated by an earthquake impact study, this paper develops new tests with several invariant properties for functional data. For multi-sample functional ANOVA (mfANOVA), based on local polynomial regression, exact local and global ANOVA decompositions into within- and between-group of variations are obtained. A local mfANOVA test is developed to examine differences in a local neighborhood, and combining local quantities, a global mfANOVA test statistic is formed. We show that both the local and global mfANOVA test statistics are location, scale, and translation invariant, allow interchanging the order of smoothing and ANOVA projection, and have asymptotic F -distributions under the null hypotheses with the Gaussian assumption. This paper contributes to the literature by being the first, to our knowledge, to study mfANOVA tests with several invariant properties. Simulation studies are presented to compare the proposed global mfANOVA test with some existing procedures. Application to an earthquake impact study in Taiwan reveals that when an earthquake in 2016 resulted in closed highways, the patterns of traffic flows were significantly different between three time periods, before the earthquake, during, and after the repair period. The information could be useful in planning for disaster preparedness.

Objective: Falun Gong (FLG) is a practice of mind and body focusing on moral character improvement along with meditative exercises. This 2002 pilot study explored perceived health status, medical resource utilization and related factors among Taiwanese FLG practitioners, compared to the general Taiwanese norm estimated by the 2001 National Health Interview Survey (NHIS). Methods: This cross-sectional, observational study was based on a voluntary, paper-based survey conducted from October 2002 to February 2003 using the same Taiwanese SF-36 instrument employed by the NHIS. Primary outcomes included eight SF-36 domain scores and the number of medical visits. One-sample t-tests, one-way ANOVA and multivariate linear regression analyses were performed. Results: The response rate was 75.6% (1,210/1,600). Compared to the norm, the study cohort had significantly higher scores in six of eight SF-36 domains across gender and age (p, Five tables

Background: The COVID-19 outbreak on the Diamond Princess (DP) cruise ship provided empirical data to study the transmission potential of COVID-19 under quarantine with the presence of asymptomatic cases. Methods: We studied the changes in R0 on the DP from January 21 to February 19, 2020 based on chain-binomial models under two scenarios: no quarantine assuming a random mixing condition, and quarantine of passengers in cabins — passengers may get infected either by an infectious case in a shared cabin or by asymptomatic crew who continued to work. Results: Estimates of R0 at the beginning of the epidemic were 3.27 (95% CI, 3.02-3.54) and 3.78 (95% CI, 3.49-4.09) respectively for serial intervals of 5 and 6 days; and when quarantine started, with the reported asymptomatic ratio 0.505, R0 rose to 4.18 (95%CI, 3.86-4.52) and 4.73 (95%CI, 4.37-5.12) respectively for passengers who might be exposed to the virus due to contacts with asymptomatic crew. The overall R0 for both crew and passengers was decreased to 2.55 (95%CI, 2.36-2.76) and 2.90 (95% CI, 2.67-3.13). Results show that the higher the asymptomatic ratio is, the more infectious contacts would happen. Conclusions: We find evidence to support a US CDC report that “a high proportion of asymptomatic infections could partially explain the high attack rate among cruise ship passengers and crew.” Our study suggests that the effects of quarantine may be limited if the asymptomatic ratio is high, implying that a combination of preventive measures is needed to stop the spread of virus. .

Electric vehicles (EVs) have attracted attention all over the world because of their advantages, such as energy conservation and carbon emission reduction. Li-ion batteries (LIBs) for energy storage in EVs are used because of their high energy density. LiFePO4 is one of the most preferred cathode materials for EVs because of several advantages, such as high specific energy, long life cycle, environmental safety, and low cost. However, at high temperatures, LiFePO4 devices exhibit iron dissolution, which limits the use of LiFePO4 in EVs. This study fabricates an in operando, self-growing, solid electrolyte interphase (SEI) on the LiFePO4 electrode by using an atmospheric pressure plasma jet (APPJ) to prevent iron dissolution and extend its life cycle. The APPJ treatment results in the plasma-induced grafting of hydrophilic functional groups on the LiFePO4 surface, which are used for the in operando synthesis of an amorphous a-FePO4·H2O thin layer on the surface and subsequent electrochemical reaction with ethylene carbonate to form a unique core-shell SEI layer. Contact angle measurements and optical emission and Raman spectroscopy analyses reveal the surface characteristics of LiFePO4 after the APPJ treatment. TEM images confirm that the SEI was formed by an amorphous layer with a thickness of 2.73 nm. High-temperature (60 °C) testing reveals that the SEI considerably improved the cycle performance by suppressing iron dissolution. The present study fabricates an in operando, self-growing, core-shell SEI on a LiFePO4 electrode to improve the high-temperature performance of LIBs.

In this study, we develop nonparametric analysis of deviance tools for generalized partially linear models based on local polynomial fitting. Assuming a canonical link, we propose expressions for both local and global analysis of deviance, which admit an additivity property that reduces to analysis of variance decompositions in the Gaussian case. Chi-square tests based on integrated likelihood functions are proposed to formally test whether the nonparametric term is significant. Simulation results are shown to illustrate the proposed chi-square tests and to compare them with an existing procedure based on penalized splines. The methodology is applied to German Bundesbank Federal Reserve data.

The effects of five plant polysaccharides (PPSs) with molecular weights of ∼4000 Da and different carboxylic group (–COOH) contents on the crystal growth of calcium oxalate (CaOx) were comparatively studied. The five PPSs were obtained from Ziziphus jujuba, Auricularia auricular, Lentinan, Lycium barbarum, and Astragalus (AS-5) with –COOH contents of 6.3%, 8.9%, 9.1%, 13.6%, and 16.1%, respectively. X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy results revealed that all five PPSs inhibited calcium oxalate monohydrate (COM) growth, induced calcium oxalate dihydrate (COD) formation, and reduced crystal aggregation. The inductively coupled plasma emission spectra of the PPSs revealed increased concentration of soluble Ca2+ ions and reduced amount of CaOx precipitates. Furthermore, the PPSs increased the absolute value of zeta potential on the crystal surface and thus favorably inhibited crystal aggregation. The abilities of PPSs to inhibit COM growth and aggregation and induce COD formation are positively correlated to their –COOH contents. At 0.1–100 μg mL−1, all PPSs had low toxicity to HK-2 cells. These results indicated that these PPSs, especially AS-5 with the highest –COOH content, are potential drugs for the prevention and treatment of CaOx stones.

Objectives: Diabetic retinopathy (DR) is a common microvascular complication in both type I and type II diabetes. Several previous reports indicated the serum centration of some secretary factors were highly associated with DR. Therefore, we hypothesis regulatory SNPs (rSNPs) genotype in secretary factors may alter these gene expression and lead to DR. Methods: At first, pyrosequencing were applying to screen the SNPs which present allele frequency different in DR and DNR. Then individual genotyping was processed by Taqman assays in Taiwanese DR and DNR patients. To evaluate the effect of SNP allele on transcriptional activity, we measured promoter activity using luciferase reporter constructs. Results: We found the frequencies of the CC, CG, and GG genotype of the rs2010963 polymorphism were 15.09%, 47.14%, and 37.74% in DR and 12.90%, 19.35%, and 67.74% in DNR, respectively (p = 0.0205). The prevalence of DR was higher (p = 0.00793) in patients with the CC or CG genotype (62.26% and 32.26% for DR and DNR, respectively) compared with the patients with the GG genotype. To evaluate the effect of rs2010963-C allele on transcriptional activity, we measured promoter activity using luciferase reporter constructs. The rs2010963-C reporter showed 1.6 to 2-fold higher luciferase activity than rs2010963-G in 3 cell lines. Conclusion: Our data proposed rs2010963-C altered the expression level of VEGFA in different tissues. We suggested small increase but long term exposure to VEGFA may lead to DR finally.

Smoothing methods for curve estimation have received considerable attention in statistics with a wide range of applications. However, to our knowledge, sample size planning for testing significance of curves has not been discussed in the literature. This paper focuses on sample size calculations for nonparametric regression and partially linear models based on local linear estimators. We describe explicit procedures for sample size calculations based on non- and semi-parametric F-tests. Data examples are provided to demonstrate the use of the procedures.

BACKGROUND: The Seychelles Child Development Study has been examining the relationship between prenatal methylmercury (MeHg) exposure from consuming fish during pregnancy and child development. This study re-analyzes seven outcomes in the 17 year Main Cohort data to determine if there are nonlinear or non-homogeneous (subgroup) associations that were not identified in the linear analysis. METHODS: We adopted two statistical approaches. First, we carried out an additive nonlinear analysis assuming homogeneous prenatal MeHg-outcome relationships to explore overall associations. Second, we applied the regression tree to the Woodcock-Johnson Calculation subtest (it was significantly associated in earlier analyses) and identified 4 clusters based on covariates. Then we used additive models to assess the prenatal MeHg association in each of the four clusters for all seven outcomes. This approach assumes nonlinear associations in each cluster and non-homogeneous associations between clusters. RESULTS: The additive nonlinear analysis yielded prenatal MeHg curves similar to the linear analysis. For the regression tree analysis, the curves relating prenatal MeHg to outcomes between the 4 clusters differed and some crossed at higher prenatal MeHg levels, suggesting non-homogeneity in the upper range of exposure. Additionally, some of the curves suggested a possible non-linear relationship within the range of exposure we studied. CONCLUSION: This non-linear analysis supports the findings from the linear analysis. It shows little evidence to support an adverse association of prenatal MeHg exposure through maternal consumption of fish contaminated with natural background levels. However, the tree analysis suggests that the prenatal exposure/outcome relationship may not be homogeneous across all individuals and that some subpopulations may have an adverse association in the upper range of the exposures studied. More robust data in the higher levels of exposure in this cohort are needed to confirm this finding.

To observe the effect of chiropractics on intervertebral disk extracell matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, cellular collagen type Ⅱ (COL-Ⅱ), tissue inhibitor 1 of metalloproteinase (TIMP-1) and extracellular matrix (ECM) in the rats with cervical spondylosis, so as to explore its mechanism underlying improvement of cervical spondylosis.A total of 40 SD rats were randomized into a sham group, a model group, a chiropractics group and a mobic group, 8 rats in each one. The model was established by static-dynamic imbalance method. The rats in the chiropractics group were treated with chiropractic therapy for two courses, 14 times a day and 14 days as a course. The rats in the mobic group were treated with intragastric administration of mobic. The expression of MMP-1, MMP-3, MMP-13, COL-Ⅱ and TIMP-1 in the intervertebral disk tissue were detected by immunohistochemistry, and the protein expression of ECM was detected by Western blot.Compared with those in the sham group, the expressions of MMP-1, MMP-3, MMP-13 in the model group increased (allChiropractics may improve the degeneration in rats with cervical spondylosis by regulating intervertebral disc ECM system and relevant metabolic enzymes.

We obtained results on identifiability of mixture, mixture proportional hazards and bounded cumulative hazards (or Yakovlev) models of survival in the presence of cured (or non-susceptible) subpopulation. These results specify conditions under which model parameters can, or cannot, be estimated from the observed potentially censored survival times and thus may guide statistical modeling. The results are formulated for larger classes of models and in greater generality than previously and correct some misconceptions that exist in statistical literature on the subject. All results are supplied with rigorous self-contained proofs.

To assess short-term safety and tolerability of estrogen replacement therapy in post-menopausal women with Parkinson's disease (PD).In a multi-center randomized, double-blind, placebo-controlled pilot trial, post-menopausal women with PD and motor fluctuations received either 0.625 mg/day of conjugated equine estrogens or matching placebo for 8 weeks. The primary outcome was the ability of participants to complete the trial. Other outcome measures included adverse events and changes from baseline to Week 8 in Unified PD Rating Scale scores, "on" time, dyskinesia ratings, and neuropsychological test results.Twenty-three women (age 62.9(6.3) years, total Unified PD Rating 25.0(13.4), 8.8(6.0) years since symptom onset) were enrolled. There were no serious adverse events. One subject withdrew due to worsening of tremor and dystonia. The most commonly reported adverse events were vaginal spotting, breast enlargement and breast tenderness. The estrogen group showed improved total and motor Unified PD Rating scores although these did not reach statistical significance (mean changes from baseline, estrogen vs. placebo: Total -5.0 vs. 2.8, treatment effect = -7.8, p = 0.10; Motor -3.0 vs. 2.4, treatment effect = -5.4, p = 0.16).Estrogen replacement therapy was safe and well-tolerated over 8 weeks in post-menopausal women with advanced PD. This pilot data suggests that estrogen replacement may be associated with improvement in motor symptoms. While larger studies of longer duration are necessary to determine the effects of estrogen in PD, the complex risk/benefit profile and continued controversy surrounding estrogen are obstacles to clinical trials.

Maternal consumption of fish during the gestational period exposes the fetus to both nutrients, especially the long-chain polyunsaturated fatty acids (LCPUFAs), believed to be beneficial for fetal brain development, as well as to the neurotoxicant methylmercury (MeHg). We recently reported that nutrients present in fish may modify MeHg neurotoxicity. Understanding the apparent interaction of MeHg exposure and nutrients present in fish is complicated by the limitations of modeling methods. In this study we fit varying coefficient function models to data from the Seychelles Child Development Nutrition Study (SCDNS) cohort to assess the association of dietary nutrients and children's development. This cohort of mother-child pairs in the Republic of Seychelles had fish consumption averaging 9 meals per week. Maternal nutritional status was assessed for five different nutritional components known to be present in fish (n-3 LCPUFA, n-6 LCPUFA, iron status, iodine status, and choline) and associated with children's neurological development. We also included prenatal MeHg exposure (measured in maternal hair). We examined two child neurodevelopmental outcomes (Bayley Scales Infant Development-II (BSID-II) Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI)), each administered at 9 and at 30 months. The varying coefficient models allow the possible interactions between each nutritional component and MeHg to be modeled as a smoothly varying function of MeHg as an effect modifier. Iron, iodine, choline, and n-6 LCPUFA had little or no observable modulation at different MeHg exposures. In contrast the n-3 LCPUFA docosahexaenoic acid (DHA) had beneficial effects on the BSID-II PDI that were reduced or absent at higher MeHg exposures. This study presents a useful modeling method that can be brought to bear on questions involving interactions between covariates, and illustrates the continuing importance of viewing fish consumption during pregnancy as a case of multiple exposures to nutrients and to MeHg. The results encourage more emphasis on a holistic view of the risks and benefits of fish consumption as it relates to infant development.

Background Diabetes confers an increased risk for cardiovascular effects of airborne particles. Objective We hypothesized that inhalation of elemental carbon ultrafine particles (UFP) would activate blood platelets and vascular endothelium in people with type 2 diabetes. Methods In a randomized, double-blind, crossover trial, 19 subjects with type 2 diabetes inhaled filtered air or 50 μg/m3 elemental carbon UFP (count median diameter, 32 nm) by mouthpiece for 2 hr at rest. We repeatedly measured markers of vascular activation, coagulation, and systemic inflammation before and after exposure. Results Compared with air, particle exposure increased platelet expression of CD40 ligand (CD40L) and the number of platelet-leukocyte conjugates 3.5 hr after exposure. Soluble CD40L decreased with UFP exposure. Plasma von Willebrand factor increased immediately after exposure. There were no effects of particles on plasma tissue factor, coagulation factors VII or IX, or D-dimer. Conclusions Inhalation of elemental carbon UFP for 2-hr transiently activated platelets, and possibly the vascular endothelium, in people with type 2 diabetes.

OBJECTIVE: To estimate the efficacy of common treatments for vulvodynia: topical lidocaine monotherapy, oral desipramine monotherapy, and lidocaine-desipramine combined therapy. METHODS: A 12-week randomized, double-blinded, placebo-controlled trial was conducted on 133 vulvodynia-afflicted women assigned to four treatment arms: placebo tablets-placebo cream, desipramine tablets–placebo cream, placebo tablets–lidocaine cream, and desipramine tablets–lidocaine cream. The tampon test was selected as primary end point using a modified intention-to-treat analysis. Twelve secondary end points were also examined. At completion of the 12-week randomized phase, women were examined “open label” through 52 weeks postrandomization. RESULTS: All treatment arms reported substantial tampon-test pain reduction: 33% reduction placebo creamplacebo tablet, 20% reduction lidocaine cream–placebo tablet, 24% reduction placebo cream–desipramine tablet, and 36% reduction lidocaine cream-desipramine tablet. Compared with placebo, we found no significant difference in tampon-test pain reduction with desipramine (t=0.90;P=.37) or lidocaine (t=1.27;P=.21). Of the remaining 12 outcome measures, only the Index of Sexual Satisfaction, improved with desipramine compared with placebo (t=−2.81;P=.006). During the open-label phase, women undergoing vestibulectomy surgery reported significantly improved pain as measured by cotton swab test and the McGill Pain Scale compared with nonsurgical alternatives. CONCLUSION: Oral desipramine and topical lidocaine, as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo. Placebo or placeboindependent effects are behind the substantial pain improvement seen in all treatment allocations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068. LEVEL OF EVIDENCE: I

Studies of neurodevelopmental outcomes in offspring exposed to MeHg from maternal consumption of fish have primarily measured cognitive abilities. Reported associations have been subtle and in both adverse and beneficial directions. Changes in functional outcomes such as school achievement and behavior in exposed children and adolescents have not been examined. We undertook an assessment of school success of children in the Seychelles Child Development Study (SCDS) main cohort to determine if there were any associations with either prenatal or recent postnatal MeHg exposure. The primary endpoints were Seychelles nationally standardized end-of-year examinations given when the cohort children were 9 and 17 years of age. A subgroup (n = 215) from the main cohort was also examined at 9 years of age using a regional achievement test called SACMEQ. Prenatal MeHg exposure was 6.8 ppm in maternal hair; recent postnatal exposure was 6.09 ppm at 9 years and 8.0 ppm at 17 years, measured in child hair. Multiple linear regression analyses showed no pattern of associations between prenatal or postnatal exposure, and either the 9- or 17-year end-of-year examination scores. For the subgroup of 215 subjects who participated in the SACMEQ test, there were significant adverse associations between examination scores and postnatal exposure, but only for males. The average postnatal exposure level in child hair for this subgroup was significantly higher than for the overall cohort. These results are consistent with our earlier studies and support the interpretation that prenatal MeHg exposure at dosages achieved by mothers consuming a diet high in fish are not associated with adverse educational measures of scholastic achievement. The adverse association of educational measures with postnatal exposure in males is intriguing, but will need to be confirmed by further studies examining factors that influence scholastic achievement.

Fish consumption during pregnancy exposes the fetus to both the neurotoxicant methylmercury and nutrients known to be beneficial for brain development. When nutrient status is not measured, maternal methylmercury levels may be a partial biomarker for both toxic and nutrient exposures. It is therefore necessary to employ a flexible model—such as the partial linear model—that will allow for possible nonlinear trends of methylmercury. To enhance interpretations of fitting a partial linear model, we propose analysis of variance (ANOVA) inference tools including ANOVA decomposition and significance tests. The ANOVA decomposition explicitly gives the proportion of variation explained by the model and separates the contributions from the parametric and nonparametric components. Semiparametric F-tests are constructed based on ANOVA decomposition with the normality assumption. The proposed F-tests are applicable to testing significance of the parametric, the nonparametric, and the combination of both. The ANOVA in...

BACKGROUND Hormonal therapy is effective for advanced prostate cancer (PC) but the disease often recurs and becomes hormone-refractory. It is hypothesized that a subpopulation of cancer cells, that is, cancer stem cells (CSCs), survives hormonal therapy and leads to tumor recurrence. CD44 expression was shown to identify tumor cells with CSC features. PC contains secretory type epithelial cells and a minor population of neuroendocrine cells. Neuroendocrine cells do not express androgen receptor and are quiescent, features associated with CSCs. The purpose of the study was to determine the expression of CD44 in human PC and its relationship to neuroendocrine tumor cells. METHODS Immunohistochemistry and immunofluorescence were performed to study CD44 expression in PC cell lines, single cells from fresh PC tissue and archival tissue sections of PC. We then determined if CD44+ cells represent neuroendocrine tumor cells. RESULTS In human PC cell lines, expression of CD44 is associated with cells of NE phenotype. In human PC tissues, NE tumor cells are virtually all positive for CD44 and CD44+ cells, excluding lymphocytes, are all NE tumor cells. CONCLUSIONS Selective expression of the stem cell-associated marker CD44 in NE tumor cells of PC, in combination with their other known features, further supports the significance of such cells in therapy resistance and tumor recurrence. Prostate 69: 787–798, 2009. © 2009 Wiley-Liss, Inc.

A standardized tampon insertion and removal test, the Tampon Test provides an alternative to sexual intercourse pain as an outcome measure for vulvodynia research. We report upon the reliability, validity, and responsiveness to change of the Tampon Test as an outcome measure for vulvodynia clinical trials.Outcome measures were assessed in women enrolled in the Vulvar Vestibulitis Clinical Trial, a randomized clinical trial of oral desipramine and topical lidocaine effectiveness. Reliability estimates of the Tampon Test using the Kappa statistic evaluated week-to-week measures at baseline. Tampon Test construct and discriminant validity were assessed through correlation with other outcome measures. Patients' ability to regularly perform the Tampon Test was compared with regularity of reporting intercourse pain.During the 2-week baseline phase, women with vulvodynia reported stable mean Tampon Test scores 4.6+/-2.6 (week -2); 4.6+/-2.7 (week -1); and 4.7+/-2.8 (week 0) with moderate week-to-week reliability (weighted Kappa 0.52). Over an 8-week phase of trial intervention, change in the Tampon Test measure significantly correlated to a number of outcome measures, including daily pain (r=0.42), intercourse pain (r=0.35), cotton swab vestibular pain (r=0.38), and the Brief Pain Inventory (r=0.49). Women with vulvodynia study participants performed the Tampon Test 96.3% of the requested time, which was twofold higher adherence than intercourse pain measurement (49.7%).The Tampon Test reflects a real life experience that is reliable, with good construct validity as shown by the breadth of correlated outcome measures. The Tampon Test is an appropriate outcome measure for vulvodynia research that can be considered for use as the primary efficacy endpoint in clinical trials of treatments for vulvodynia.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068II.

In this paper, we investigate geometric properties of local polynomial regression and show that the class of global polynomial models is nested within the class of functions generated by fitting local polynomials. The geometric properties are then utilized to construct nonparametric F -tests for testing whether a regression relationship is a polynomial function. The proposed F -tests can be seen as a “calculus” extension of the classical F -tests with analysis of variance interpretations. With the normality assumption, the test statistic is shown to have asymptotic F -distributions under the null hypothesis and fixed alternatives. Simulation results illustrate that the asymptotic null F -distribution approximates well in finite sample cases and the proposed tests enjoy robustness against heteroscedasticity and non-normality as do the classical F -tests.

Local linear regression involves fitting a straight line segment over a small region whose midpoint is the target point x, and the local linear estimate at x is the estimated intercept of that straight line segment, with an asymptotic bias of order h 2 and variance of order ( nh ) - 1 (h is the bandwidth). In this paper, we propose a new estimator, the double-smoothing local linear estimator, which is constructed by integrally combining all fitted values at x of local lines in its neighborhood with another round of smoothing. The proposed estimator attempts to make use of all information obtained from fitting local lines. Without changing the order of variance, the new estimator can reduce the bias to an order of h 4 . The proposed estimator has better performance than local linear regression in situations with considerable bias effects; it also has less variability and more easily overcomes the sparse data problem than local cubic regression. At boundary points, the proposed estimator is comparable to local linear regression. Simulation studies are conducted and an ethanol example is used to compare the new approach with other competitive methods.

The mechanisms underlying the association between air pollution and cardiovascular morbidity and mortality are unknown. This study aimed to determine whether controlled exposure to elemental carbon ultrafine particles (UFP) affects electrocardiogram (ECG) parameters describing heart rate variability; repolarization duration, morphology, and variability; and changes in the ST segment. Two separate controlled studies (12 subjects each) were performed using a crossover design, in which each subject was exposed to filtered air and carbon UFP for 2 hours. The first protocol involved 2 exposures to air and 10 microg/m(3) (approximately 2 x 10(6) particles/cm(3), count median diameter approximately 25 nm, geometric standard deviation approximately 1.6), at rest. The second protocol included 3 exposures to air, 10, and 25 microg/m(3) UFP (approximately 7 x 10(6) particles/cm(3)), with repeated exercise. Each subject underwent a continuous digital 12-lead ECG Holter recording to analyze the above ECG parameters. Repeated measures analysis of variance (ANOVA) was used to compare tested parameters between exposures. The observed responses to UFP exposure were small and generally not significant, although there were trends indicating an increase in parasympathetic tone, which is most likely also responsible for trends toward ST elevation, blunted QTc shortening, and increased variability of T-wave complexity after exposure to UFP. Recovery from exercise showed a blunted response of the parasympathetic system after exposure to UFP in comparison to air exposure. In conclusion, transient exposure to 10-25 microg/m(3) ultrafine carbon particles does not cause marked changes in ECG-derived parameters in young healthy subjects. However, trends are observed indicating that some subjects might be susceptible to air pollution, with a response involving autonomic modulation of the heart and repolarization of the ventricular myocardium.

The Seychelles Child Development Study was designed to test the hypothesis that prenatal exposure to MeHg from maternal consumption of a diet high in fish is detrimental to child neurodevelopment. To date, no consistent pattern of adverse associations between prenatal exposure and children's development has appeared. In a comprehensive review of developmental studies involving MeHg, a panel of experts recommended a more consistent use of the same endpoints across studies to facilitate comparisons. Both the SCDS and the Faeroe Islands studies administered the Bender Visual Motor Gestalt Test. However, the method of test administration and scoring used was different. We repeated the test on the SCDS Main Study children (mean age 10.7 years) using the same testing and scoring procedure reported by the Faeroe studies to obtain Copying Task and Reproduction Task scores. We found no association between prenatal MeHg exposure and Copying Task scores which was reported from the Faeroese study. However, our analysis did show a significant adverse association between MeHg and Reproduction Task scores with all the data (p = 0.04), but not when the single outlier was removed (p = 0.07). In a population whose exposure to MeHg is from fish consumption, we continue to find no consistent adverse association between MeHg and visual motor coordination.

Background Ultrafine particles (UFP) may contribute to the cardiovascular effects of exposure to particulate air pollution, partly because of their relatively efficient alveolar deposition and potential to enter the pulmonary vascular space. Objectives This study tested the hypothesis that inhalation of elemental carbon UFP alters systemic vascular function. Methods Sixteen healthy subjects (mean age, 26.9 ± 6.5 years) inhaled air or 50 μg/m3 elemental carbon UFP by mouthpiece for 2 hr, while exercising intermittently. Measurements at preexposure baseline, 0 hr (immediately after exposure), 3.5 hr, 21 hr, and 45 hr included vital signs, venous occlusion plethysmography and reactive hyperemia of the forearm, and venous plasma nitrate and nitrite levels. Results Peak forearm blood flow after ischemia increased 3.5 hr after exposure to air but not UFP (change from preexposure baseline, air: 9.31 ± 3.41; UFP: 1.09 ± 2.55 mL/min/100 mL; t-test, p = 0.03). Blood pressure did not change, so minimal resistance after ischemia (mean blood pressure divided by forearm blood flow) decreased with air, but not UFP [change from preexposure baseline, air: −0.48 ± 0.21; UFP: 0.07 ± 0.19 mmHg/mL/min; analysis of variance (ANOVA), p = 0.024]. There was no UFP effect on pre-ischemia forearm blood flow or resistance, or on total forearm blood flow after ischemia. Venous nitrate levels were significantly lower after exposure to carbon UFP compared with air (ANOVA, p = 0.038). There were no differences in venous nitrite levels. Conclusions Inhalation of 50 μg/m3 carbon UFP during intermittent exercise impairs peak forearm blood flow during reactive hyperemia in healthy human subjects.

Background: The Seychelles Child Development Study (SCDS) has been longitudinally following a cohort of over 700 children enrolled in 1989. Their mothers consumed a diet high in fish during pregnancy. Repeated examination of the SCDS cohort at six different ages through age 11 years has shown no pattern of adverse effects. Some early appearing beneficial associations between both prenatal and postnatal hair MeHg and several child development endpoints were noted. We hypothesized these might be related to micronutrients in the fish, but they were not found when the children reached middle school age. These findings suggest that the associations observed between MeHg and developmental outcomes may vary with developmental stage. Method: We examined the main cohort of the SCDS to determine if this might be true using a longitudinal multiple regression analysis design that focused on those endpoints that were repeatedly measured at different ages. The primary endpoint analyzed was global cognition, involving a measure of developmental quotient or IQ. Secondary analyses included other domains such as Reading and Mathematics scholastic achievement, social behavior, and memory. Analyses involved two different approaches, one including incorporation of a passage of time variable, the other including a difference of scores across time points. Results: No significant associations were found between prenatal MeHg exposure and any of the repeatedly measured endpoints. Conclusions: These results suggest that even when individual subject variance is controlled there was no consistent pattern of associations between child development outcomes and prenatal exposures to MeHg from maternal consumption of a diet high in fish. The Seychellois diet contains about 10 times more ocean fish than is typically consumed by US citizens. Our primary focus on IQ should further inform growing scientific interest in the analysis of the risks and benefits of fish consumption on overall cognitive ability.

Ultrafine particles (UFPs; aerodynamic diameter100 nm) may contribute to the respiratory and cardiovascular morbidity and mortality associated with particulate air pollution. We tested the hypothesis that inhalation of carbon UFPs has vascular effects in healthy and asthmatic subjects, detectable as alterations in blood leukocyte expression of adhesion molecules. Healthy subjects inhaled filtered air and freshly generated elemental carbon particles (count median diameter approximately 25nm, geometric standard deviation approximately 1.6), for 2 hr, in three separate protocols: 10 microg/m3 at rest, 10 and 25 microg/m3 with exercise, and 50 microg/m3 with exercise. In a fourth protocol, subjects with asthma inhaled air and 10 microg/m3 UFPs with exercise. Peripheral venous blood was obtained before and at intervals after exposure, and leukocyte expression of surface markers was quantitated using multiparameter flow cytometry. In healthy subjects, particle exposure with exercise reduced expression of adhesion molecules CD54 and CD18 on monocytes and CD18 and CD49d on granulocytes. There were also concentration-related reductions in blood monocytes, basophils, and eosinophils and increased lymphocyte expression of the activation marker CD25. In subjects with asthma, exposure with exercise to 10 microg/m3 UFPs reduced expression of CD11b on monocytes and eosinophils and CD54 on granulocytes. Particle exposure also reduced the percentage of CD4+ T cells, basophils, and eosinophils. Inhalation of elemental carbon UFPs alters peripheral blood leukocyte distribution and expression of adhesion molecules, in a pattern consistent with increased retention of leukocytes in the pulmonary vascular bed.

The objective of this paper is to propose a friction test method to evaluate the performance of different kinds of lubricants and determine their coefficients of friction in tube hydroforming processes. A self-designed apparatus is used to conduct the experiments of friction tests. The coefficient of friction between the tube and the die at the guiding zone is determined. The effects of the internal pressure and the axial feeding velocity on the friction forces and coefficients of friction for various lubricants are discussed. From the experimental results, it is known that MoS2 corresponding to a coefficient of friction of 0.018 is the best lubricant among the evaluated lubricants during tube hydroforming processes.

The authors propose "kernel spline regression," a method of combining spline regression and kernel smoothing by replacing the polynomial approximation for local polynomial kernel regression with the spline basis. The new approach retains the local weighting scheme and the use of a bandwidth to control the size of local neighborhood. The authors compute the bias and variance of the kernel linear spline estimator, which they compare with local linear regression. They show that kernel spline estimators can succeed in capturing the main features of the underlying curve more effectively than local polynomial regression when the curvature changes rapidly. They also show through simulation that kernel spline regression often performs better than ordinary spline regression and local polynomial regression. (Examples use motorcycle impact injury data.

Studies of the association between prenatal methylmercury exposure from maternal fish consumption and neurodevelopmental test scores in the Seychelles Child Development Study have not found adverse effects through age 9 years. The analysis for the most recent 9-year data (Lancet 361 (2003) 1686) employed conventional linear regression models. In this study we reanalyzed the same Seychelles 9-year data using semiparametric additive models with different degrees of smoothing to explore whether nonlinear effects of prenatal exposure were present. Of 21 endpoints in the linear analysis, we chose only those with a two-tailed P value less than 0.2 for the effect of prenatal exposure. Six endpoints met the criterion. A nonlinear effect was identified with the more smooth model for only one endpoint. The test for an overall effect of prenatal exposure was also significant, with a P value of 0.04, while the corresponding P value in the linear regression analysis was 0.08. The nonlinear curve appeared to be nearly flat when the level was below approximately 12 ppm in maternal hair, with a linear trend above that level, suggesting a possible adverse effect in the uppermost range of prenatal exposure included in this cohort. Because of the descriptive nature of semiparametric additive models, the P values are not precise, and certainly there are fewer data above 12 ppm. We conclude that this reanalysis supports the primary linear analysis, showing little evidence for a prenatal adverse effect.

Summary In a linear model, the effect of a continuous explanatory variable may vary across groups defined by a categorical variable, and the variable itself may be subject to measurement error. This suggests a linear measurement error model with slope-by-factor interactions. The variables that are defined by such interactions are neither continuous nor discrete, and hence it is not immediately clear how to fit linear measurement error models when interactions are present. This paper gives a corollary of a theorem of Fuller for the situation of correcting measurement errors in a linear model with slope-by-factor interactions. In particular, the error-corrected estimate of the coefficients and its asymptotic variance matrix are given in a more easily assessable form. Simulation results confirm the asymptotic normality of the coefficients in finite sample cases. We apply the results to data from the Seychelles Child Development Study at age 66 months, assessing the effects of exposure to mercury through consumption of fish on child development for females and males for both prenatal and post-natal exposure.

Studies of the effects of environmental exposures on human health typically require estimation of both exposure and outcome. Standard methods for the assessment of the association between exposure and outcome include multiple linear regression analysis, which assumes that the outcome variable is observed with error, while the levels of exposure and other explanatory variables are measured with complete accuracy, so that there is no deviation of the measured from the actual value. The term measurement error in this discussion refers to the difference between the actual or true level and the value that is actually observed. In the investigations of the effects of prenatal methylmercury (MeHg) exposure from fish consumption on child development, the only way to obtain a true exposure level (producing the toxic effect) is to ascertain the concentration in fetal brain, which is not possible. As is often the case in studies of environmental exposures, the measured exposure level is a biomarker, such as the average maternal hair level during gestation. Measurement of hair mercury is widely used as a biological indicator for exposure to MeHg and is the only indicator that has been calibrated against the target tissue, the developing brain. Variability between the measured and the true values in explanatory variables in a multiple regression analysis can produce bias, leading to either over or underestimation of regression parameters (slopes). Fortunately, statistical methods known as measurement error models (MEM) are available to account for measurement errors in explanatory variables in multiple regression analysis, and these methods can provide an (either “unbiased” or “bias-corrected”) estimate of the unknown outcome/exposure relationship. In this paper, we illustrate MEM analysis by reanalyzing data from the 5.5-year test battery in the Seychelles Child Development Study, a longitudinal study of prenatal exposure to MeHg from maternal consumption of a diet high in fish. The use of the MEM approach was made possible by the existence of independent, calibration data on the magnitude of the variability of the measurement error deviations for the biomarker of prenatal exposure used in this study, the maternal hair level. Our reanalysis indicated that adjustment for measurement errors in explanatory variables had no appreciable effect on the original results.

Summary Introduction Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is aternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. Methods We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The ssociation between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Findings Mean prenatal MeHg exposure was 6·9 parts per million (SD 4·5ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure as associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. Interpretation These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption.

We investigate the connections between local polynomial regression, mixed models, and penalized trigonometric series regression. Expressing local polynomial regression in a projection framework, we derive equivalent kernels for both the interior and boundary points. For interior points, it is shown that the asymptotic bias decreases as the order of polynomial increases. Then we show that, under some conditions, the local polynomial projection approach admits an equivalent mixed model formulation where the fixed effects part includes the polynomial functions. The random effects part in the representation is shown to be the trigonometric series asymptotically. The connections are extended to partial linear models and additive models. These results suggest a new smoothing approach using a combination of unpenalized polynomials and penalized trigonometric functions. We illustrate the potential usefulness of the new approach with real data analysis.

This article shows how to smoothly "monotonize" standard kernel estimators of hazard rate, using bootstrap weights. Our method takes a variety of forms, depending on choice of kernel estimator and on the distance function used to define a certain constrained optimization problem. We confine attention to a particularly simple kernel approach and explore a range of distance functions. It is straightforward to reduce "quadratic" inequality constraints to "linear" equality constraints, and so our method may be implemented using little more than conventional Newton-Raphson iteration. Thus, the necessary computational techniques are very familiar to statisticians. We show both numerically and theoretically that monotonicity, in either direction, can generally be imposed on a kernel hazard rate estimator regardless of the monotonicity or otherwise of the true hazard rate. The case of censored data is easily accommodated. Our methods have straightforward extension to the problem of testing for monotonicity of hazard rate, where the distance function plays the role of a test statistic.

Several new tests are proposed for examining the adequacy of a family of parametric models against large nonparametric alternatives. These tests formally check if the bias vector of residuals from parametric fits is negligible by using the adaptive Neyman test and other methods. The testing procedures formalize the traditional model diagnostic tools based on residual plots. We examine the rates of contiguous alternatives that can be detected consistently by the adaptive Neyman test. Applications of the procedures to the partially linear models are thoroughly discussed. Our simulation studies show that the new testing procedures are indeed powerful and omnibus. The power of the proposed tests is comparable to the F-test statistic even in the situations where the F test is known to be suitable and can be far more powerful than the F-test statistic in other situations. An application to testing linear models versus additive models is also discussed.

It has been shown that a smoothing spline estimate is an equivalent kernel estimate. In this paper, we show that both the Nadaraya–Watson and local linear kernel estimators are equivalent penalized estimators.