Assembly of Genome and Resequencing Provide Insights into Genetic Differentiation between Parents of Hulong Hybrid Grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂).

The Hulong hybrid grouper was bred from the brown-marbled grouper (Epinephelus fuscoguttatus) ♀ and the giant grouper (E. lanceolatus) ♂, combining the advantageous traits of both parents. Possessing an excellent performance, this hybrid's cultivation promotes the development of the grouper industry. Its male parent, the giant grouper, possesses the fastest growth and the largest body size among all coral-reef-dwelling fish. This species is not only an economically important species in marine aquaculture, but it is also an ideal male parent in the interspecific crossing of grouper species. In the present study, a high-quality chromosome-level genome of the giant grouper was constructed with a total length of 1.06 Gb, consisting of 24 chromosomes and 69 scaffolds. To analyze the genetic differences between the parents of the Hulong hybrid grouper, the structural variations (SVs) between both parental genomes were detected, and a total of 46,643 SVs were obtained. High-quality SNPs were identified from resequencing data. There were significant differences between the two genomes, and the average FST reached 0.685. A total of 234 highly differentiated regions were detected with an FST > 0.9. The protein-coding genes involved in SVs and highly differentiated regions were significantly enriched in metabolic pathways, including fatty metabolism, carbohydrate metabolism, amino acid metabolism and the TCA cycle. These genes may be related to the differences in feeding preferences and the ability to digest carbohydrates between the two grouper species under natural conditions. In addition, protein-coding genes related to the cell cycle and p53-signaling pathway were also detected. These genes may play important roles in the regulation of body size and growth performance. This research provides genomic resources for further breeding works and evolutionary analyses.

Augmented likelihood for incorporating auxiliary information into left-truncated data.

Time-to-event data are often subject to left-truncation. Lack of consideration of the sampling condition will introduce bias and loss in efficiency of the estimation. While auxiliary information from the same or similar cohorts may be available, challenges arise due to the practical issue of accessibility of individual-level data and taking account of various sampling conditions for different cohorts. In this paper, we introduce a likelihood-based method to incorporate information from auxiliary data to eliminate the left-truncation problem and improve efficiency. A one-step Monte-Carlo Expectation-Maximization algorithm is developed to calculate an augmented likelihood through creating pseudo-data sets which extend the form and conditions of the observed sample. The method is illustrated by both a real dataset and simulation studies.

Multistate analysis from cross-sectional and auxiliary samples.

Epidemiological studies routinely involve cross-sectional sampling of a population comprised of individuals progressing through life history processes. We consider features of a cross-sectional sample in terms of the intensity functions of a progressive multistate disease process under stationarity assumptions. The limiting values of estimators for regression coefficients in naive logistic regression models are studied, and simulations confirm the key asymptotic results that are relevant in finite samples. We also consider the need for and the use of data from auxiliary samples, which enable one to fit the full multistate life history process. We conclude with an application to data from a national cross-sectional sample assessing marker effects on psoriatic arthritis among individuals with psoriasis.

Mitigating bias from intermittent measurement of time-dependent covariates in failure time analysis.

Cox regression models are routinely fitted to examine the association between time-dependent markers and a failure time when analyzing data from clinical registries. Typically, the marker values are measured periodically at clinic visits with the recorded value carried forward until the next assessment. We examine the asymptotic behavior of estimators from Cox regression models under this observation and data handling scheme when the true relationship is based on a Cox model using the current value of the marker. Specifically, we explore the impact of the marker process dynamics, the clinic visit intensity, and the marginal failure rate on the limiting value of the estimator of the marker effect from the Cox model. We also illustrate how a joint multistate model that accommodates intermittent observation of the time-varying marker can be formulated. Simulation studies demonstrate that the finite sample performance of the naive estimator aligns with the asymptotic results and shows good performance of the estimators from the joint model. We apply both methods to data from a study of bone markers and their effect on the development of skeletal complications in metastatic cancer.

Design of cancer trials based on progression-free survival with intermittent assessment.

Therapeutic advances in cancer mean that it is now impractical to performed phase III randomized trials evaluating experimental treatments on the basis of overall survival. As a result, the composite endpoint of progression-free survival has been routinely adopted in recent years as it is viewed as enabling a more timely and cost-effective approach to assessing the clinical benefit of novel interventions. This article considers design of cancer trials directed at the evaluation of treatment effects on progression-free survival. In particular, we derive sample size criteria based on an illness-death model that considers cancer progression and death jointly while accounting for the fact that progression is assessed only intermittently. An alternative approach to design is also considered in which the sample size is derived based on a misspecified Cox model, which uses the documented time of progression as the progression time rather than dealing with the interval censoring. Simulation studies show the validity of the proposed methods.

Tracing studies in cohorts with attrition: Selection models for efficient sampling.

Cohort studies of chronic diseases involve recruitment and longitudinal follow-up of affected individuals with a view to studying the effect of risk factors on disease progression and death. When the time to withdrawal from the cohort is conditionally independent of the disease process the primary consequence is a loss of information on the parameters of interest. This loss can sometimes be mitigated through the conduct of tracing studies in which a subsample of those lost to follow up are contacted and some information is obtained on their disease and survival status. We describe the use of selection models to sample individuals for tracing who will yield more efficient estimators than those obtained by simple random sampling. Efficient sampling schemes featuring cost constraints are also developed and shown to perform well. An application to data from the University of Toronto Psoriatic Arthritis Cohort illustrates how to apply the method in a real setting.

Bias in progression-free survival analysis due to intermittent assessment of progression.

Cancer clinical trials are routinely designed to assess the effect of treatment on disease progression and death, often in terms of a composite endpoint called progression-free survival. When progression status is known only at periodic assessment times, the progression time is interval censored, and complications arise in the analysis of progression-free survival. Despite the advances in methods for dealing with interval-censored data, naive methods such as right-endpoint imputation are widely adopted in this setting. We examine the asymptotic and empirical properties of estimators of the marginal progression-free survival functions and associated treatment effects under this scheme. Specifically, we explore the determinants of the asymptotic bias and point out that there is typically a loss in power of tests for treatment effects.

The association between memory, COVID-19 testing, and COVID-19 incidence in middle-aged and older adults: a prospective analysis of the CLSA.

We investigated the association between pre-COVID-19 memory function and (a) receipt of a COVID-19 test and (b) incidence of COVID-19 using the COVID-19 Questionnaire Study (CQS) of the Canadian Longitudinal Study on Aging (CLSA). The CQS included 28,565 middle-aged and older adults. We regressed receipt of a COVID-19 test on participants' immediate and delayed recall memory scores and re-ran the regression models with COVID-19 incidence as the outcome. All regression models were adjusted for sociodemographic, lifestyle, and health covariates. In the analytical sample (n = 21,930), higher delayed recall memory (better memory) was significantly associated with lower COVID-19 incidence. However, this association was not significant for immediate recall memory. Immediate and delayed recall memory were not associated with receipt of a COVID-19 test. Health policymakers and practitioners may viewmemory status as a potential risk for COVID-19. Memory status may not be a barrier to COVID-19 testing.

A longitudinal evaluation of the relationship between first morning urinary and salivary cortisol.

UNLABELLED: Cortisol is one of the most frequently used stress biomarkers in humans. Urine and saliva are the matrices of choice to longitudinally monitor cortisol levels. Salivary and urinary cortisol are often discussed as though they provide similar information. However, the relationship between "free" cortisol levels in urine (nonconjugated) and saliva (non-protein-bound) has yet to be properly evaluated using naturalistic designs. OBJECTIVES: To investigate the longitudinal relationship between salivary cortisol (SC) and first morning urinary cortisol (FMUC), and to compare the advantages and disadvantages of these matrices in assessing longitudinal changes in cortisol secretion using naturalistic designs. METHODS: Cortisol levels from 31 healthy, Kakchiquel Mayan women in Guatemala were compared in one first morning urine (FMU) and four saliva specimens collected daily across three alternate days. Linear mixed-effect regression models including fixed and random effects were used to analyze the repeated-measures data. RESULTS: FMUC levels (16.04-242.18 ng/ml) were higher than SC levels (0.21-5.16 ng/ml). A small but statistically significant relationship was found between FMUC and SC (each 1 ng/ml increase in FMUC predicted a 0.1% increase in SC; P < 0.05). CONCLUSIONS: Nonconjugated FMUC levels are related to non-protein-bound SC levels collected throughout the day. FMU presents several advantages over saliva for the longitudinal assessment of cortisol in naturalistic studies. Cortisol levels are about 53-fold higher in FMU than in saliva, which makes between- and within-individual variation easier to detect, and FMUC levels are less likely to be affected by confounders than diurnal SC levels.

Where are the NGOs and why? The distribution of health and development NGOs in Bolivia.

BACKGROUND: The presence and influence of nongovernmental organizations (NGOs) in the landscape of global health and development have dramatically increased over the past several decades. The distribution of NGO activity and the ways in which contextual factors influence the distribution of NGO activity across geographies merit study. This paper explores the distribution of NGO activity, using Bolivia as a case study, and identifies local factors that are related to the distribution of NGO activity across municipalities in Bolivia. METHODS: The research question is addressed using a geographic information system (GIS) and multiple regression analyses of count data. We used count data of the total number of NGO projects across Bolivian municipalities to measure NGO activity both in general and in the health sector specifically and national census data for explanatory variables of interest. RESULTS: This study provides one of the first empirical analyses exploring factors related to the distribution of NGO activity at the national scale. Our analyses show that NGO activity in Bolivia, both in general and health-sector specific, is distributed unevenly across the country. Results indicate that NGO activity is related to population size, extent of urbanization, size of the indigenous population, and health system coverage. Results for NGO activity in general and health-sector specific NGO activity were similar. CONCLUSIONS: The uneven distribution of NGO activity may suggest a lack of co-ordination among NGOs working in Bolivia as well as a lack of co-ordination among NGO funders. Co-ordination of NGO activity is most needed in regions characterized by high NGO activity in order to avoid duplication of services and programmes and inefficient use of limited resources. Our findings also indicate that neither general nor health specific NGO activity is related to population need, when defined as population health status or education level or poverty levels. Considering these results we discuss broader implications for global health and development and make several recommendations relevant for development and health practice and research.

Who is stressed? Comparing cortisol levels between individuals.

UNLABELLED: Cortisol is the most commonly used biomarker to compare physiological stress between individuals. Its use, however, is frequently inappropriate. Basal cortisol production varies markedly between individuals. Yet, in naturalistic studies that variation is often ignored, potentially leading to important biases. OBJECTIVES: Identify appropriate analytical tools to compare cortisol across individuals and outline simple simulation procedures for determining the number of measurements required to apply those methods. METHODS: We evaluate and compare three alternative methods (raw values, Z-scores, and sample percentiles) to rank individuals according to their cortisol levels. We apply each of these methods to first morning urinary cortisol data collected thrice weekly from 14 cycling Mayan Kaqchiquel women. We also outline a simple simulation to estimate appropriate sample sizes. RESULTS: Cortisol values varied substantially across women (ranges: means: 1.9-2.7; medians: 1.9-2.8; SD: 0.26-0.49) as did their individual distributions. Cortisol values within women were uncorrelated. The accuracy of the rankings obtained using the Z-scores and sample percentiles was similar, and both were superior to those obtained using the cross-sectional cortisol values. Given the interindividual variation observed in our population, 10-15 cortisol measurements per participant provide an acceptable degree of accuracy for across-women comparisons. CONCLUSIONS: The use of single raw cortisol values is inadequate to compare physiological stress levels across individuals. If the distributions of individuals' cortisol values are approximately normal, then the standardized ranking method is most appropriate; otherwise, the sample percentile method is advised. These methods may be applied to compare stress levels across individuals in other populations and species.

Cognitive Reserve and Mild Cognitive Impairment: Predictors and Rates of Reversion to Intact Cognition vs Progression to Dementia.

BACKGROUND AND OBJECTIVES: Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling. METHODS: We estimated instantaneous transition rates between NC, MCI, and dementia after accounting for transition to death across up to 12 assessments in the Nun Study, a cohort study of religious sisters aged 75+ years. We estimated RRs of reversion vs progression for age, APOE, and potential cognitive reserve indicators: education, academic performance (high school grades), and written language skills (idea density, grammatical complexity). RESULTS: Of the 619 participants, 472 were assessed with MCI during the study period. Of these 472, 143 (30.3%) experienced at least one reverse transition to NC, and 120 of the 143 (83.9%) never developed dementia (mean follow-up = 8.6 years). In models adjusted for age group and APOE, higher levels of education more than doubled the RR ratio of reversion vs progression. Novel cognitive reserve indicators were significantly associated with a higher adjusted RR of reversion vs progression (higher vs lower levels for English grades: RR ratio = 1.83; idea density: RR ratio = 3.93; and grammatical complexity: RR ratio = 5.78). DISCUSSION: Knowledge of frequent reversion from MCI to NC may alleviate concerns of inevitable cognitive decline in those with MCI. Identification of characteristics predicting the rate of reversion from MCI to NC vs progression from MCI to dementia may guide population-level interventions targeting these characteristics to prevent or postpone MCI and dementia. Research on cognitive trajectories would benefit from incorporating predictors of reverse transitions and competing events, such as death, into statistical modeling. These results may inform the design and interpretation of MCI clinical trials, given that a substantial proportion of participants may experience improvement without intervention.

Cardiovascular autonomic dysfunction is associated with executive dysfunction and poorer quality of life in progressive supranuclear palsy-Richardson's syndrome.

BACKGROUND: Autonomic dysfunction in progressive supranuclear palsy (PSP) is not uncommon but is easily neglected. OBJECTIVE: We evaluated blood pressure (BP) profiles in PSP patients and aimed to determine the associations between BP variability and cognition and quality of life. METHODS: Consecutive patients diagnosed with PSP were enrolled in this cross-sectional study. All patients underwent 24-hour ambulatory blood pressure monitoring, office blood pressure measurements, and comprehensive clinical assessments. RESULTS: We enrolled 31 PSP patients. Ten (32.3%) patients presented with reverse dipping, 10 (32.3%) presented with reduced dipping, and 11 (35.5%) presented with normal dipping. Additionally, 19 (61.3%) patients had supine hypertension, and no patients had orthostatic hypotension. In the entire PSP cohort, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) score, Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score, and daytime systolic BP (SBP) standard deviation explained 61.5% (adjusted R2) of the variance in Parkinson's Disease Questionnaire-39 (PDQ-39) scores. In the PSP with Richardson's syndrome group, the daytime SBP coefficient of variation and Mini-Mental State Examination score accounted for 33.9% of the variance in Frontal Assessment Battery scores. The MDS-UPDRS III score, 24-hour SBP coefficient of variation, and SCOPA-AUT score explained 77.6% of the variance in PDQ-39 scores. CONCLUSIONS: Greater BP variability was associated with executive dysfunction and poorer quality of life in patients with PSP. A high prevalence of abnormal dipping patterns indicated circadian disruption in patients with PSP.

Does ratification of human-rights treaties have effects on population health?

Human-rights treaties indicate a country's commitment to human rights. Here, we assess whether ratification of human-rights treaties is associated with improved health and social indicators. Data for health (including HIV prevalence, and maternal, infant, and child [<5 years] mortalities) and social indicators (child labour, human development index, sex gap, and corruption index), gathered from 170 countries, showed no consistent associations between ratification of human-rights treaties and health or social outcomes. Established market economy states had consistently improved health compared with less wealthy settings, but this was not associated with treaty ratification. The status of treaty ratification alone is not a good indicator of the realisation of the right to health. We suggest the need for stringent requirements for ratification of treaties, improved accountability mechanisms to monitor compliance of states with treaty obligations, and financial assistance to support the realisation of the right to health.

Regression analysis with a misclassified covariate from a current status observation scheme.

Naive use of misclassified covariates leads to inconsistent estimators of covariate effects in regression models. A variety of methods have been proposed to address this problem including likelihood, pseudo-likelihood, estimating equation methods, and Bayesian methods, with all of these methods typically requiring either internal or external validation samples or replication studies. We consider a problem arising from a series of orthopedic studies in which interest lies in examining the effect of a short-term serological response and other covariates on the risk of developing a longer term thrombotic condition called deep vein thrombosis. The serological response is an indicator of whether the patient developed antibodies following exposure to an antithrombotic drug, but the seroconversion status of patients is only available at the time of a blood sample taken upon the discharge from hospital. The seroconversion time is therefore subject to a current status observation scheme, or Case I interval censoring, and subjects tested before seroconversion are misclassified as nonseroconverters. We develop a likelihood-based approach for fitting regression models that accounts for misclassification of the seroconversion status due to early testing using parametric and nonparametric estimates of the seroconversion time distribution. The method is shown to reduce the bias resulting from naive analyses in simulation studies and an application to the data from the orthopedic studies provides further illustration.

[The application of operating room quality backward system in instrument place management].

OBJECTIVE: Improvement of the surgery instrument's clean quality, the optimized preparation way, reasonable arrangement in groups, raising the working efficiency. METHOD: We use the quality backward system into the instrument clean, the pack and the preparation way's question, carry on the analysis and the optimization, and appraise the effect after trying out 6 months. RESULTS: After finally the way optimized, instrument clean quality distinct enhancement; The flaws in the instrument clean, the pack way and the total operating time reduce; the contradictory between nurses and the cleans arising from the unclear connection reduces, the satisfaction degree of nurse and doctor to the instrument enhances. CONCLUSIONS: Using of operating room quality backward system in the management of the instrument clean, the pack and the preparation way optimized, may reduce flaws in the work and the waste of human resources, raise the working efficiency.

Thermal decomposition behavior and kinetics of nanocomposites at low-modified ZnO content.

In this study, a titanate coupling agent (TCA) was used to modify the surface of nano ZnO. The thermal properties of room temperature vulcanized silicone rubber (RTV) nanocomposites with modified nano ZnO were compared at nano-filler weight fractions ranging from 0% to 2%. The results indicated that the titanate coupling agent was successfully grafted on the surface of nano ZnO. The size and shape of the nanoparticles were not changed after modification and all particles were about 36 nm. With increasing amounts of nanoparticles, the initial thermal decomposition temperature increased from 344.6 °C to 420 °C and reached maximum at 1.5% ZnO addition. The thermal decomposition process of RTV can be divided into three different stages. In the first stage, the temperatures at maximum decomposition rate (T 1max) for the five samples were similar. In the second and third stages, T 2max and T 3max increased 79.1 °C and 88.9 °C, respectively, upon addition of the modified nano ZnO. The thermal decomposition kinetics results showed that the activation energy (E α) of RTV was lower than that of 1% ZnO/RTV at the low thermal conversion rate (α). The average E α values of the two samples were similar, at 144.29 kJ mol-1 and 146.78 kJ mol-1, respectively. The kinetic energy index (n) of RTV was 3.84. Compared to pure RTV, 1% ZnO/RTV showed a more complex thermal decomposition process, as its n value was 0.66 higher than that of RTV. Comparing E α and n values, it was found that the nanocomposites were less likely to transform into an activated complex due to their higher potential energy barrier.

The influence mechanism of nanoparticles on the dielectric properties of epoxy resin.

In order to study the influence mechanism of nanoparticles on the dielectric properties of epoxy resin materials for composite insulators under different nanoparticle filling amounts, the free volume, dielectric relaxation, breakdown strength and trap distribution of the samples were tested by positron annihilation lifetime spectroscopy, breakdown strength, broadband dielectric spectroscopy (BDS) and thermally stimulated current (TSC). The results show that the limiting effect of nanoparticles rapidly reduced the number of traps in the amorphous zone of materials at a low filling amount. As a result, the free path of carriers was increased and the concentration of free volume was decreased, which can limit the injection and transportation of carriers, resulting in the increase of material breakdown strength. At a high filling amount, a large number of interfacial deep traps were introduced into the nanoparticles, and the carrier free volume concentration and size were reduced. The traps inside the material were mainly interfacial deep traps. Under the action of an external electric field, a hetero polar charge was formed on the other end to cause electric field distortion, thus the breakdown field strength of the material was weakened.

A multistate model for bivariate interval-censored failure time data.

SUMMARY: Interval-censored life-history data arise when the events of interest are only detectable at periodic assessments. When interest lies in the occurrence of two such events, bivariate-interval censored event time data are obtained. We describe how to fit a four-state Markov model useful for characterizing the association between two interval-censored event times when the assessment times for the two events may be generated by different inspection processes. The approach treats the two events symmetrically and enables one to fit multiplicative intensity models that give estimates of covariate effects as well as relative risks characterizing the association between the two events. An expectation-maximization (EM) algorithm is described for estimation in which the maximization step can be carried out with standard software. The method is illustrated by application to data from a trial of HIV patients where the events are the onset of viral shedding in the blood and urine among individuals infected with cytomegalovirus.

Anterior optic nerve capillary blood flow response to diurnal variation of mean ocular perfusion pressure in early untreated primary open-angle glaucoma.

PURPOSE: To examine the impact of diurnal variation in intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) on the variation in anterior optic nerve capillary blood flow (BF) in patients with untreated early primary open-angle glaucoma (uPOAG) and healthy volunteers. METHODS: Fourteen patients with uPOAG (age, 56.3 +/- 12 years [SD]; seven men) and 14 normal subjects (age, 57.6 +/- 9.9 years; five men) were examined. Diurnal IOP, systolic (SBP) and diastolic (DBP) blood pressures, and optic nerve head (ONH) topography were measured every hour; and diurnal BF was measured by flowmeter every 2 hours between 0700 and 2200 hours. A perfusion image analyzer was used to calculate the mean BF within the rim (mean rim flow, MRF). The local flow (LF) was calculated using the median and mean flow rates within a 10 x 10-pixel window placed on the rim in the area of maximum topography fluctuation (MTF). The MOPP was then calculated. Mixed-effect linear models were used to analyze the repeated measures data in which both fixed and random effects were included. RESULTS: IOP, BP, and MOPP had significant diurnal variation (P < 0.040). LF measured at the sector of MTF significantly changed in patients with uPOAG (P = 0.006) but not in normal subjects (P = 0.660). MRF did not show significant diurnal change in either group (P = 0.130, P = 0.770). LF increased significantly after lunch in the uPOAG group (P = 0.001). SBP had a significant effect on LF over the course of the day in the uPOAG group (P = 0.043). The diurnal change in IOP, BP, and MOPP did not have a significant effect on MTF in either group. In uPOAG, the local flow, in areas of greatest topographical change, correlated inversely with IOP at 0700 hours (P < or = 0.002). CONCLUSIONS: The mean rim flow did not change during the day, implying that the anterior optic nerve capillary blood flow was autoregulated in both normal subjects and in patients with uPOAG, despite significant changes in IOP and MOPP. However, the regions of greatest diurnal change in rim topography (MTF) had significant diurnal change in capillary blood flow in patients with uPOAG but not in normal subjects.