Residual Heterogeneity Research Articles

Radiation and circulatory disease.

Exposure to therapeutic doses of ionizing radiation is associated with damage to the heart and coronary arteries. However, only recently have studies with high-quality individual dosimetry data allowed this risk to be quantified while also adjusting for concomitant chemotherapy, and medical and lifestyle risk factors. At lower levels of exposure the evidence is less clear. In this article I review radiation-associated risks of circulatory disease in groups treated with radiotherapy for malignant and non-malignant disease, and in occupationally- or environmentally-exposed groups receiving rather lower levels of radiation dose, also for medical diagnostic purposes. Results of a meta-analysis suggest that excess relative risks per unit dose for various types of heart disease do not exhibit statistically significant (p>0.2) heterogeneity between studies. Although there are no marked discrepancies between risks derived from the high-dose therapeutic and medical diagnostic studies and from the moderate/low dose occupational and environmental studies, at least for ischemic heart disease and stroke there are indications of larger risks per unit dose for lower dose rate and fractionated exposures. Risks for stroke and other types of circulatory disease are significantly more variable (p<0.0001), possibly resulting from confounding and effect-modification by well known (but unobserved) risk factors. Adjustment for any of mean dose, dose fractionation or age at exposure results in the residual heterogeneity for cerebrovascular disease becoming non-significant. The review provides strong evidence in support of a causal association between both low and high dose radiation exposure and most types of circulatory disease.

Lifetime Prevalence of Suicide Attempts Among Sexual Minority Adults by Study Sampling Strategies: A Systematic Review and Meta-Analysis.

Previous reviews have demonstrated a higher risk of suicide attempts for lesbian, gay, and bisexual (LGB) persons (sexual minorities), compared with heterosexual groups, but these were restricted to general population studies, thereby excluding individuals sampled through LGB community venues. Each sampling strategy, however, has particular methodological strengths and limitations. For instance, general population probability studies have defined sampling frames but are prone to information bias associated with underreporting of LGB identities. By contrast, LGB community surveys may support disclosure of sexuality but overrepresent individuals with strong LGB community attachment. To reassess the burden of suicide-related behavior among LGB adults, directly comparing estimates derived from population- versus LGB community-based samples. In 2014, we searched MEDLINE, EMBASE, PsycInfo, CINAHL, and Scopus databases for articles addressing suicide-related behavior (ideation, attempts) among sexual minorities. We selected quantitative studies of sexual minority adults conducted in nonclinical settings in the United States, Canada, Europe, Australia, and New Zealand. Random effects meta-analysis and meta-regression assessed for a difference in prevalence of suicide-related behavior by sample type, adjusted for study or sample-level variables, including context (year, country), methods (medium, response rate), and subgroup characteristics (age, gender, sexual minority construct). We examined residual heterogeneity by using τ(2). We pooled 30 cross-sectional studies, including 21,201 sexual minority adults, generating the following lifetime prevalence estimates of suicide attempts: 4% (95% confidence interval [CI] = 3%, 5%) for heterosexual respondents to population surveys, 11% (95% CI = 8%, 15%) for LGB respondents to population surveys, and 20% (95% CI = 18%, 22%) for LGB respondents to community surveys (Figure 1). The difference in LGB estimates by sample type persisted after we accounted for covariates with meta-regression. Sample type explained 33% of the between-study variability. Regardless of sample type examined, sexual minorities had a higher lifetime prevalence of suicide attempts than heterosexual persons; however, the magnitude of this disparity was contingent upon sample type. Community-based surveys of LGB people suggest that 20% of sexual minority adults have attempted suicide. Accurate estimates of sexual minority health disparities are necessary for public health monitoring and research. Most data describing these disparities are derived from 2 sample types, which yield different estimates of the lifetime prevalence of suicide attempts. Additional studies should explore the differential effects of selection and information biases on the 2 predominant sampling approaches used to understand sexual minority health.

Lifetime Prevalence of Suicide Attempts Among Sexual Minority Adults by Study Sampling Strategies: A Systematic Review and Meta-Analysis

Background. Previous reviews have demonstrated a higher risk of suicide attempts for lesbian, gay, and bisexual (LGB) persons (sexual minorities), compared with heterosexual groups, but these were restricted to general population studies, thereby excluding individuals sampled through LGB community venues. Each sampling strategy, however, has particular methodological strengths and limitations. For instance, general population probability studies have defined sampling frames but are prone to information bias associated with underreporting of LGB identities. By contrast, LGB community surveys may support disclosure of sexuality but overrepresent individuals with strong LGB community attachment. Objectives. To reassess the burden of suicide-related behavior among LGB adults, directly comparing estimates derived from population- versus LGB community–based samples. Search methods. In 2014, we searched MEDLINE, EMBASE, PsycInfo, CINAHL, and Scopus databases for articles addressing suicide-related behavior (ideation, attempts) among sexual minorities. Selection criteria. We selected quantitative studies of sexual minority adults conducted in nonclinical settings in the United States, Canada, Europe, Australia, and New Zealand. Data collection and analysis. Random effects meta-analysis and meta-regression assessed for a difference in prevalence of suicide-related behavior by sample type, adjusted for study or sample-level variables, including context (year, country), methods (medium, response rate), and subgroup characteristics (age, gender, sexual minority construct). We examined residual heterogeneity by using τ2. Main results. We pooled 30 cross-sectional studies, including 21 201 sexual minority adults, generating the following lifetime prevalence estimates of suicide attempts: 4% (95% confidence interval [CI] = 3%, 5%) for heterosexual respondents to population surveys, 11% (95% CI = 8%, 15%) for LGB respondents to population surveys, and 20% (95% CI = 18%, 22%) for LGB respondents to community surveys ( Figure 1 ). The difference in LGB estimates by sample type persisted after we accounted for covariates with meta-regression. Sample type explained 33% of the between-study variability. Author’s conclusions. Regardless of sample type examined, sexual minorities had a higher lifetime prevalence of suicide attempts than heterosexual persons; however, the magnitude of this disparity was contingent upon sample type. Community-based surveys of LGB people suggest that 20% of sexual minority adults have attempted suicide. Public health implications. Accurate estimates of sexual minority health disparities are necessary for public health monitoring and research. Most data describing these disparities are derived from 2 sample types, which yield different estimates of the lifetime prevalence of suicide attempts. Additional studies should explore the differential effects of selection and information biases on the 2 predominant sampling approaches used to understand sexual minority health.

Nutritional status in older persons according to healthcare setting: A systematic review and meta-analysis of prevalence data using MNA®

Old persons are more likely to suffer from malnutrition, which may result in higher dependency in activities of daily living. We aimed to provide a quantitative synthesis of prevalence data on malnutrition and its risk as assessed by the Mini Nutritional Assessment across different healthcare settings. The association between nutritional status and setting-related level of dependence was also investigated. Non-interventional studies published as full-text articles in English up to 31th December 2014 were searched for in PubMed and by reviewing references of eligible articles. Meta-analysis and meta-regression of potential sources of heterogeneity were conducted. A total of 240 studies/795 citations - providing 258 setting-specific prevalence estimates (113,967 subjects) - fulfilled inclusion criteria for meta-analysis. Prevalence of malnutrition differed significantly across the healthcare settings considered: community, 3.1% (95%CI, 2.3-3.8); outpatients, 6.0% (95%CI, 4.6-7.5); home-care services, 8.7% (95%CI, 5.8-11.7); hospital, 22.0% (95%CI, 18.9-22.5); nursing homes, 17.5% (95%CI, 14.3-20.6); long-term care, 28.7% (95%CI, 21.4-36.0); rehabilitation/sub-acute care, 29.4% (95%CI, 21.7-36.9). For every setting significant heterogeneity in individual study results was observed (I2 ≥80%, P<0.001) and meta-regression showed that study quality was the most important determinant. Finally, meta-regression of all the studies included showed that both malnutrition and its risk were directly associated with the setting-related level of dependence (P<0.001). However, despite multiple adjustments, residual heterogeneity remained high. We provided updated estimates of malnutrition and its risk in different healthcare settings. Although the level of dependence appears to be an important determinant, heterogeneity in individual study results remained substantially unexplained. The cause-effect relationship between nutritional status and level of dependence deserves further investigation.

On the specification of prior distributions for variance components in disease mapping models

In this paper, we consider the problem of specifying priors for the variance components in the Bayesian analysis of the Besag-York-Mollie model, a model that is popular among epidemiologists for disease mapping. The model encompasses two sets of random effects: one spatially structured to model spatial autocorrelation and the other spatially unstructured to describe residual heterogeneity. In this model, prior specification for variance components is an important problem because these priors maintain their influence on the posterior distributions of relative risks when mapping rare diseases. We propose using generalised inverse Gaussian priors, a broad class of distributions that includes many distributions commonly used as priors in this context, such as inverse gammas. We discuss the prior parameter choice with the aim of balancing the prior weight of the two sets of random effects on total variation and controlling the amount of shrinkage. The suggested prior specification strategy is compared to popular alternatives using a simulation exercise and applications to real data sets.

Fluorescence investigations on choline phospholipid binding and chemical unfolding of HSP-1/2, a major protein of horse seminal plasma

Seminal fibronectin type-II (Fn-II) proteins interact with choline phospholipids present on the sperm plasma membrane and play a crucial role in sperm capacitation. Crystal structure of phosphorylcholine (PrC) complex of PDC-109, the major bovine Fn-II protein, together with fluorescence spectroscopic studies has shown that tryptophan residues are crucial for its specific interaction with choline phospholipids. In the present study, the heterogeneity and microenvironment of tryptophan residues in HSP-1/2, a major protein of horse seminal plasma (which is homologous to PDC-109) were investigated in the native state, in the presence of PrC and phosphatidylcholines (PCs) with short (valeryl, C-5) and long (myristoyl, C-14) chains, and upon denaturation using fluorescence quenching, time-resolved fluorescence and red-edge excitation shift (REES) measurements. The results obtained show that the environment of tryptophan residues in HSP-1/2 is more heterogeneous as compared to that in PDC-109. Binding of choline containing ligands afforded a protection to the tryptophan residues with the shielding order being: PrC≤divalaroyl PC<dimyristoyl PC. REES value obtained for HSP-1/2 (3.5nm) is smaller than that of observed for PDC-109 (4nm) and binding to PrC and DVPC reduced the REES to 1nm. HSP-1/2 exhibits only partial unfolding with chemical denaturants with no cooperativity, whereas complete unfolding was observed in the presence of 10mM dithiothreitol, indicating that disulfide linkages prevent complete unfolding of the protein. In the presence of PrC the transition midpoints shifted to higher concentrations of the denaturant together with a broadening of the sigmoidal transitions, indicating that ligand binding as well as polydispersity modulate the unfolding process.

Survival outcomes of supportive care versus dialysis therapies for elderly patients with end-stage kidney disease: A systematic review and meta-analysis.

Elderly people comprise a large and growing proportion of the global dialysis population. Regional differences in rates of dialysis in the elderly suggest multiple factors influence treatment decision-making including beliefs about the relative benefits and harms of dialysis and supportive (non-dialysis) care. We therefore systematically reviewed the literature reporting survival of elderly patients treated with either treatment pathway. Systematic review and meta-analysis of cohort studies or randomized controlled trials identified in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials published before July 2014. Survival by treatment modality was calculated. Subgroup analyses by study design, study size, patient age and cohort era were conducted. Eighty-nine studies published between 1976 and 2014 reported on 294 921 elderly end-stage kidney disease (ESKD) patients. There was a paucity of data for supportive care (724 patients or 0.2% of the total patients) and supportive care studies were susceptible to lead-time bias. One-year survival for elderly patients treated with undifferentiated dialysis was 73.0% (95% confidence interval (CI) 66.3-79.7%), 78.4% (95% CI 75.2-81.6) for haemodialysis and 77.9% (95% CI 73.8-81.9) for peritoneal dialysis. Supportive care patients had a 1-year survival of 70.6% (95% CI 63.3-78.0%). Residual heterogeneity remained within individual treatment modalities despite subgroup analyses. While the available literature demonstrates a broadly similar 1-year survival in elderly ESKD patients, it does not allow a confident estimate of the relative survival benefits of dialysis or supportive care. This uncertainty needs urgent attendance by further prospective data, which avoid bias and allow comparisons of quality of life and survival.

Adequacy and verifiability of pharmaceutical mixtures and dose units by variographic analysis (Theory of Sampling) – A call for a regulatory paradigm shift

In spite of intense efforts in the last 20 years, the current state of affairs regarding evaluation of adequacy of pharmaceutical mixing is at an impressive standstill, characterized by two draft guidances, one withdrawn, and the other never approved. We here analyze the regulatory, scientific and technological situation and suggest a radical, but logical approach calling for a paradigm shift regarding sampling of pharmaceutical blends. In synergy with QbD/PAT efforts, blend uniformity testing should only be performed with properly designed sampling that can guarantee representativity—in contrast to the current deficient thief sampling. This is necessary for suitable in-process specifications and dosage units meeting desired specifications. The present exposé shows how process sampling based on the Theory of Sampling (TOS) constitutes a new asset for regulatory compliance, providing procedures that suppress hitherto adverse sampling errors. We identify that the optimal sampling location is after emptying the blender, guaranteeing complete characterisation of the residual heterogeneity. TOS includes variographic analysis that decomposes the effective total sampling and analysis error (TSE+TAE) from the variability of the manufacturing process itself. This approach provides reliable in-process characterization allowing independent approval or rejection by the Quality Control unit. The science-based sampling principles presented here will facilitate full control of blending processes, including whether post-blending segregation influences the material stream that reaches the tabletting feed-frame.

Rituximab Maintenance for Aggressive B Cell Lymphoma Improves Outcomes Only in Rituximab Naive Patients, Results from a Meta-Analysis

Whilst maintenance therapy with rituximab has been established its role as for follicular lymphoma with high tumor burden, its clinical relevance in aggressive lymphoma still remains to be elucidated due to controversial results of previous studies. In order to address this issue, we conducted a meta-analysis targeting CD20 positive diffuse large B cell lymphoma. We collected prospective randomized trials where case cohorts were administered with single agent rituximab as maintenance therapy for responding patients (PR or better) to induction treatments with or without consolidative autologous stem cell transplantation (ASCT), and were compared with control cohorts just followed with observation. Out of the 387 candidate reports, we extracted four relevant papers. Rituximab maintenance was placed as the first-line treatment scheme in three studies and second-line or later in one. The pooled estimates of the effect were calculated using random-effect model according to the method of Der Simonian-Laird with inverse variance weighting. Hazard ratio (HR) was selected as measures for responses, and risk difference (RD) for adverse effects. When HR was not available for a given study, it was estimated using methods described by Tierney et al. We assessed heterogeneity of the trial results using a chi-square test of heterogeneity and the I2 measure of inconsistency. Data of the 1546 patients of aggressive lymphoma from four studies comprising of 773 subjects each in maintenance and observation arms. Overall, rituximab maintenance had marginal impact on event-free survival (hazard ratio (HR): 0.80, 95% confidential interval (CI): 0.63 - 1.02, p=0.0719). Heterogeneity among all the trials was not statistically significant (p=0.19, I2=37.01%). To investigate the factors associated with significant impact of rituximab maintenance, we performed subset analyses according to various parameters inherent to study design of each report. No use of rituximab as part of induction treatment prior to randomization was significantly associated with better EFS in the rituximab maintenance arm (HR: 0.57, 95% CI: 0.35 - 0.93, p=0.024). By contrast, rituximab maintenance had almost no impact on outcomes when patients had already received rituximab before (HR: 0.91, 95%CI: 0.73 - 1.15, p=0.437). Furthermore, rituximab maintenance had positive effect when used in the first-line treatment scheme (HR: 0.72, 95% CI: 0.58 - 0.89, p=0.0026). When ASCT was not included in the treatments prior to randomization, rituximab maintenance significantly improved EFS (HR: 0.71, 95% CI: 0.56 - 0.91, p=0.0057). In order to examine relative impact of these parameters, we conducted meta-analyses using mixed-effects model treating these parameters (ASCT in prior treatment, rituximab in prior treatment, in first-line scheme) as categorical moderators. Prior rituximab administration before randomization was the sole significant factor (beta=0.6017, p=0.0253). Notably, in this model, residual heterogeneity disappeared almost completely (I2=0.0%, test for residual heterogeneity p=0.62), suggesting that the three parameters representing the difference of study design accounts for almost all of variety in effect-sizes among them. This suggests that rituximab included in induction therapy is sufficient to exert its role for responding aggressive lymphoma. Rituximab maintenance was associated with neutropenia (RD: 0.06, 95% CI: 0.01 - 0.12) and marginal increase of infection (RD: 0.14, 95% CI: -0.08 - 0.36). In conclusion, rituximab maintenance was not associated with better EFS in overall subjects. It has positive effect on EFS only when rituximab was not used in the induction therapy, which is a rare situation nowadays, negating practical usefulness of adding rituximab maintenance for aggressive lymphoma. [Display omitted] DisclosuresTsurumi:Chugai Pharmaceuticals: Speakers Bureau.

Surface modeling of soil antibiotics

Large numbers of livestock and poultry feces are continuously applied into soils in intensive vegetable cultivation areas, and then some veterinary antibiotics are persistent existed in soils and cause health risk. For the spatial heterogeneity of antibiotic residues, developing a suitable technique to interpolate soil antibiotic residues is still a challenge. In this study, we developed an effective interpolator, high accuracy surface modeling (HASM) combined vegetable types, to predict the spatial patterns of soil antibiotics, using 100 surface soil samples collected from an intensive vegetable cultivation area located in east of China, and the fluoroquinolones (FQs), including ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX), were analyzed as the target antibiotics. The results show that vegetable type is an effective factor to be combined to improve the interpolator performance. HASM achieves less mean absolute errors (MAEs) and root mean square errors (RMSEs) for total FQs (NFX+CFX+EFX), NFX, CFX and EFX than kriging with external drift (KED), stratified kriging (StK), ordinary kriging (OK) and inverse distance weighting (IDW). The MAE of HASM for FQs is 55.1μg/kg, and the MAEs of KED, StK, OK and IDW are 99.0μg/kg, 102.8μg/kg, 106.3μg/kg and 108.7μg/kg, respectively. Further, RMSE simulated by HASM for FQs (CFX, EFX and NFX) are 106.2μg/kg (88.6μg/kg, 20.4μg/kg and 39.2μg/kg), and less 30% (27%, 22% and 36%), 33% (27%, 27% and 43%), 38% (34%, 23% and 41%) and 42% (32%, 35% and 51%) than the ones by KED, StK, OK and IDW, respectively. HASM also provides better maps with more details and more consistent maximum and minimum values of soil antibiotics compared with the measured data. The better performance can be concluded that HASM takes the vegetable type information as global approximate information, and takes local sampling data as its optimum control constraints.

The ‘Expanded HIV care in opioid substitution treatment’ (EHOST) cluster-randomized, stepped-wedge trial: A study protocol

The public health response to HIV/AIDS has turned its focus onto optimizing health care system delivery to maximize case identification, access and sustained engagement in antiretroviral treatment (ART). Opioid Agonist Treatment (OAT) provides a critical opportunity for HIV testing and linkage to ART. The EHOST study is a cluster-randomized, stepped-wedge trial to evaluate a prescriber-focused intervention to increase HIV testing rates, and optimize ART engagement and retention outcomes among individuals engaged in OAT. The study will encompass all drug treatment clinics currently admitting patients for the treatment of opioid use disorder across the province of British Columbia, encompassing an estimated 90% of the OAT caseload. The trial will be executed over a 24-month period, with groups of clinics receiving the intervention in 6-month intervals. Evaluation of the proposed intervention's effectiveness will focus on three primary outcomes: (i) the HIV testing rate among those not known to be HIV positive; (ii) the rate of ART initiation among those not on ART; and (iii) the rate of ART continuation among those on ART. A difference-in-differences analytical framework will be applied to estimate the intervention's effect. This approach will assess site-specific changes in primary outcomes across clusters while adjusting for potential residual heterogeneity in patient case mix, volume, and quality of care across clinics. Statistical analysis of outcomes will be conducted entirely with linked population-level administrative health datasets. Facilitated by established collaborations between key stakeholders across the province, the EHOST intervention promises to optimize HIV testing and care within a marginalized and hard-to-reach population.

Accuracy and precision of minimally-invasive cardiac output monitoring in children: a systematic review and meta-analysis.

Several minimally-invasive technologies are available for cardiac output (CO) measurement in children, but the accuracy and precision of these devices have not yet been evaluated in a systematic review and meta-analysis. We conducted a comprehensive search of the medical literature in PubMed, Cochrane Library of Clinical Trials, Scopus, and Web of Science from its inception to June 2014 assessing the accuracy and precision of all minimally-invasive CO monitoring systems used in children when compared with CO monitoring reference methods. Pooled mean bias, standard deviation, and mean percentage error of included studies were calculated using a random-effects model. The inter-study heterogeneity was also assessed using an I(2) statistic. A total of 20 studies (624 patients) were included. The overall random-effects pooled bias, and mean percentage error were 0.13±0.44lmin(-1) and 29.1%, respectively. Significant inter-study heterogeneity was detected (P<0.0001, I(2)=98.3%). In the sub-analysis regarding the device, electrical cardiometry showed the smallest bias (-0.03lmin(-1)) and lowest percentage error (23.6%). Significant residual heterogeneity remained after conducting sensitivity and subgroup analyses based on the various study characteristics. By meta-regression analysis, we found no independent effects of study characteristics on weighted mean difference between reference and tested methods. Although the pooled bias was small, the mean pooled percentage error was in the gray zone of clinical applicability. In the sub-group analysis, electrical cardiometry was the device that provided the most accurate measurement. However, a high heterogeneity between studies was found, likely due to a wide range of study characteristics.

Estimates of genetic parameters for growth traits in Brahman cattle using random regression and multitrait models.

Random regression models (RRM) and multitrait models (MTM) were used to estimate genetic parameters for growth traits in Brazilian Brahman cattle and to compare the estimated breeding values obtained by these 2 methodologies. For RRM, 78,641 weight records taken between 60 and 550 d of age from 16,204 cattle were analyzed, and for MTM, the analysis consisted of 17,385 weight records taken at the same ages from 12,925 cattle. All models included the fixed effects of contemporary group and the additive genetic, maternal genetic, and animal permanent environmental effects and the quadratic effect of age at calving (AAC) as covariate. For RRM, the AAC was nested in the animal's age class. The best RRM considered cubic polynomials and the residual variance heterogeneity (5 levels). For MTM, the weights were adjusted for standard ages. For RRM, additive heritability estimates ranged from 0.42 to 0.75, and for MTM, the estimates ranged from 0.44 to 0.72 for both models at 60, 120, 205, 365, and 550 d of age. The maximum maternal heritability estimate (0.08) was at 140 d for RRM, but for MTM, it was highest at weaning (0.09). The magnitude of the genetic correlations was generally from moderate to high. The RRM adequately modeled changes in variance or covariance with age, and provided there was sufficient number of samples, increased accuracy in the estimation of the genetic parameters can be expected. Correlation of bull classifications were different in both methods and at all the ages evaluated, especially at high selection intensities, which could affect the response to selection.

Surgical site infection after valvular or coronary artery bypass surgery: 2008–2011 French SSI national ISO-RAISIN surveillance

Multisite information regarding surgical site infection (SSI) rates for cardiac surgery programmes is not widely available. Ward characteristics that may affect outcomes have not been analysed previously. To determine individual- and ward-level factors associated with SSI occurrence after coronary artery bypass grafting (CABG) and valvular surgery. A dataset from the French national SSI database ISO-RAISIN 2008-2011 was used. Only adult patients were included. A standardized questionnaire was completed for each patient who underwent surgery, and patients with and without SSI were characterized. Patients and ward risk factors for SSI were analysed using a multilevel logistic regression model with SSI as binary outcome (two levels: patient and ward). Out of 8569 patients from 39 wards, the SSI rate was 2.2%. Micro-organisms were isolated in 144 patients (74%): 35% coagulase-negative staphylococci (N=51), 23% Staphylococcus aureus (N=33), 6% Escherichia coli (N=8). Higher probability of SSI was associated with the duration of preoperative hospitalization, the duration of follow-up, the duration of surgery >75th percentile and the SSI rate in the surgery ward. The residual heterogeneity between wards (median odds ratio: 1.53) was as relevant as duration of preoperative hospitalization (odds ratio: 1.57). Although patient risk factors were more strongly associated with SSI occurrence, this study provided evidence for the existence of a ward-level effect. This should be taken into account when considering possible corrective interventions.

Estimating total sampling error for near infrared spectroscopic analysis of pharmaceutical blends—theory of sampling to the rescue

Author Summary: A replication experiment was performed to validate a stream sampling method for a pharmaceutical powder blend. A 1.5 kg powder blend was prepared and an in-house developed feeder was used to divide into six sub-samples of approximately 250 g. Each 250 g sub-sample (1/6 total blender lot volume) was deposited along a rig of 3 meter length. A validated near infrared (NIR) spectroscopic method was used to determine the drug concentration as the powder deposited in the rig moved at a linear velocity of 10 mm/sec. The depth of penetration of the NIR radiation was 1.2 mm and the sample volume analysed was approximately 180 mg. The MPE (minimum practical error) obtained with the system was 0.04% w/w acetaminophen (APAP), which was considered excellent for the system. The replicate analysis of the powder deposition provided 390 measurements of drug concentration, with a mean APAP concentration of 14.93% (w/w) and a relative standard deviation (RSD) of 5.20%. Replicate measurements (n = 650) of the powder deposited along a single rig of 3 m length &#x00D7;10 provided an RSD of 2.23%, attributable to deposition (outflow) heterogeneity. Finally, static replicate analysis of the measurement error alone amounted to an RSD of 0.14%. The embedded replicate experiments elucidated all sources of variation in a sampling system for pharmaceutical powder blends, and proved reliable and highly sensitive in identifying areas of non-acceptable residual heterogeneity (dead zones).

Mixture regression models for closed population capture–recapture data

In capture-recapture studies, the use of individual covariates has been recommended to get stable population estimates. However, some residual heterogeneity might still exist and ignoring such heterogeneity could lead to underestimating the population size (N). In this work, we explore two new models with capture probabilities depending on both covariates and unobserved random effects, to estimate the size of a population. Inference techniques including Horvitz-Thompson estimate and confidence intervals for the population size, are derived. The selection of a particular model is carried out using the Akaike information criterion (AIC). First, we extend the random effect model of Darroch et al. (1993, Journal of American Statistical Association 88, 1137-1148) to handle unit level covariates and discuss its limitations. The second approach is a generalization of the traditional zero-truncated binomial model that includes a random effect to account for an unobserved heterogeneity. This approach provides useful tools for inference about N, since key quantities such as moments, likelihood functions and estimates of N and their standard errors have closed form expressions. Several models for the unobserved heterogeneity are available and the marginal capture probability is expressed using the Logit and the complementary Log-Log link functions. The sensitivity of the inference to the specification of a model is also investigated through simulations. A numerical example is presented. We compare the performance of the proposed estimator with that obtained under model Mh of Huggins (1989 Biometrika 76, 130-140).

Elucidating the effects of arginine and lysine on a monoclonal antibody C-terminal lysine variation in CHO cell cultures.

C-terminal lysine variants are commonly observed in monoclonal antibodies (mAbs) and found sensitive to process conditions, especially specific components in culture medium. The potential roles of media arginine (Arg) and lysine (Lys) in mAb heavy chain C-terminal lysine processing were investigated by monitoring the lysine variant levels under various Arg and Lys concentrations. Both Arg and Lys were found to significantly affect lysine variant level. Specifically, lysine variant level increased from 18.7 to 31.8 % when Arg and Lys concentrations were increased from 2 to 10 mM. Since heterogeneity of C-terminal lysine residues is due to the varying degree of proteolysis by basic carboxypeptidases (Cps), enzyme (basic Cps) level, pH conditions, and product (Arg and Lys) inhibition, which potentially affect the enzymatic reaction, were investigated under various Arg and Lys conditions. Enzyme level and pH conditions were found not to account for the different lysine variant levels, which was evident from the minimal variation in transcription level and intracellular pH. On the other hand, product inhibition effect of Arg and Lys on basic Cps was evident from the notable intracellular and extracellular Arg and Lys concentrations comparable with Ki values (inhibition constant) of basic Cps and further confirmed by cell-free assays. Additionally, a kinetic study of lysine variant level during the cell culture process enabled further characterization of the C-terminal lysine processing.

Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents.

The literature on the prevalence of mental disorders affecting children and adolescents has expanded significantly over the last three decades around the world. Despite the field having matured significantly, there has been no meta-analysis to calculate a worldwide-pooled prevalence and to empirically assess the sources of heterogeneity of estimates. We conducted a systematic review of the literature searching in PubMed, PsycINFO, and EMBASE for prevalence studies of mental disorders investigating probabilistic community samples of children and adolescents with standardized assessments methods that derive diagnoses according to the DSM or ICD. Meta-analytical techniques were used to estimate the prevalence rates of any mental disorder and individual diagnostic groups. A meta-regression analysis was performed to estimate the effect of population and sample characteristics, study methods, assessment procedures, and case definition in determining the heterogeneity of estimates. We included 41 studies conducted in 27 countries from every world region. The worldwide-pooled prevalence of mental disorders was 13.4% (CI 95% 11.3-15.9). The worldwide prevalence of any anxiety disorder was 6.5% (CI 95% 4.7-9.1), any depressive disorder was 2.6% (CI 95% 1.7-3.9), attention-deficit hyperactivity disorder was 3.4% (CI 95% 2.6-4.5), and any disruptive disorder was 5.7% (CI 95% 4.0-8.1). Significant heterogeneity was detected for all pooled estimates. The multivariate metaregression analyses indicated that sample representativeness, sample frame, and diagnostic interview were significant moderators of prevalence estimates. Estimates did not vary as a function of geographic location of studies and year of data collection. The multivariate model explained 88.89% of prevalence heterogeneity, but residual heterogeneity was still significant. Additional meta-analysis detected significant pooled difference in prevalence rates according to requirement of funcional impairment for the diagnosis of mental disorders. Our findings suggest that mental disorders affect a significant number of children and adolescents worldwide. The pooled prevalence estimates and the identification of sources of heterogeneity have important implications to service, training, and research planning around the world.

Female Weddell seals show flexible strategies of colony attendance related to varying environmental conditions.

Many animal life cycles involve movements among different habitats to fulfill varying resource demands. There are inherent costs associated with such movements, and the decision to leave or stay at a given location ought to be motivated by the benefits associated with potential target habitats. Because movement patterns, especially those associated with reproduction, can have important implications for the success (survival, reproduction) of individual animals, and therefore a population's dynamics, it is important to identify and understand their sources of variation (environmental and individual). Here, using a mark-recapture, multistate modeling approach, we investigated a set of a priori hypotheses regarding sources and patterns of variation in breeding-colony attendance for Weddell seal (Leptonychotes weddellii) females on sabbatical from pup production. For such females, colony attendance might be motivated by predation avoidance and positive social interactions related to reproduction, but some costs, such as reduced foraging opportunities or aggressive interactions with conspecifics, might also exist. We expected these benefits and costs to vary with a female's condition and the environment. Results revealed that the probability of being absent from colonies was higher (1) in years when the extent of local sea ice was larger, (2) for the youngest and oldest individuals, and (3) for females with less reproductive experience. We also found substantial levels of residual individual heterogeneity in these rates. Based on our a priori predictions, we postulate that the decision to attend breeding colonies or not is directly influenced by an individual's physiological condition, as well as by the ice-covered distance to good foraging areas, availability of predator-free haul-out sites, and the level of negative interactions with conspecifics inside colonies. Our results support the idea that in iteroparous species, and colonial animals in particular, seasonal and temporary movements from/to reproductive sites represent flexible behavioral strategies that can play an important role in coping with environmental variability.

Modeling Spatial Correlation Structure in Sugarcane (Saccharum spp.) Multi-Environment Trials

Comparative multi-environment trials (METs) of sugarcane genotypes are frequently conducted using a randomized complete-block design (RCBD) within environments. However, blocking does not always ensure spatial variation control because of differential competition for resources among neighboring genotypes. Heterogeneity within trials may also cause between-trial heterocedasticity. This work aims to evaluate different linear mixed models (LMMs) that enable the analysis of spatial correlation and residual heterogeneity among trials for both tons of cane per hectare (TCH) and sucrose content (SC%) in three series of multi-environmental trials conducted to evaluate advanced sugarcane clones. A total of 16 sugarcane trials conducted at different sites and in different crop cycles (age) were analyzed. Individual (age×site combination) and multi-environment analyses were performed. For SC%, the classic RCBD analysis within trial was adequate. For TCH, the anisotropic autoregressive model of order 1 (AR1×AR1) was the best to compare genotype means in most trials, allowing gain in information equivalent, on average, to the addition of 1.6 replicates to the original design. In the case of multi-environment analysis, the AR1×AR1 within-trial with among-trial heteroscedasticity was the best model to compare variety means, both for TCH and SC%. The results showed how a more appropriate mixed model would help avoid commission of judgment errors in sugarcane variety recommendations.