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The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
To examine the incidence of asthma in adult patients with major depressive disorder (MDD).
From the National Health Insurance database of Taiwan, we identified 30 169 adult patients who were newly diagnosed with MDD between 2000 and 2010. Individuals without depression were randomly selected four times and frequency matched for sex, age and year of diagnosis. Both cohorts were followed-up for the occurrence of asthma up to the end of 2011. Adjusted hazard ratios (aHRs) of asthma were estimated using the Cox proportional hazards method.
The overall incidence of asthma was 1.91-fold higher in the MDD cohort than in the non-depression cohort (7.55 v. 3.96 per 1000 person-years), with an aHR of 1.66 (95% confidence interval (CI) 1.55–1.78). In both cohorts, the incidence of asthma was higher in patients and controls who were female, aged, with comorbidities and users of aspirin or beta-adrenergic receptor blockers. No significant difference was observed in the occurrence of asthma between patients with MDD treated with selective serotonin reuptake inhibitors (SSRIs) and those treated with non-SSRIs (SSRIs to non-SSRIs aHR = 1.03, 95% CI 0.91–1.17).
Adult patients with MDD are at a higher risk of asthma than those without depression are.
Spectroscopic Observations were made to study 42 emission line objects. The analysis of these long slit spectra shows that 15 out of 42 galaxies are blue compact galaxies (BCGs). 21 of them are starforming or HII galaxies and 3 were found to be normal galaxies.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
In this paper, the effect of phosphorus diffusion and hydrogen passivation on the material properties of laser crystallised silicon on glass is investigated. Photoluminescence imaging, as well as Hall effect and Suns-Voc techniques are applied for the characterisation of laser crystallized silicon thin-film material properties. Hall effect as well as Suns-Voc measurements supports the photoluminescence imaging results; phosphorus diffusion and hydrogen passivation of laser crystallized films improves the overall material quality. Hydrogen passivation is more effective at improving the electronic properties of the laser crystallized films than phosphorus diffusion. Hydrogen passivated samples improved the photoluminescence intensity even further by a factor of 3. In addition, a correlation between photoluminescence intensity and open-circuit voltage is demonstrated: samples with highest photoluminescence intensity (1678 counts/s), gave the highest voltage (530 mV). Hall effect measurement shows a significant improvement in the bulk material, with carrier mobility increasing from 208 cm2/Vs to 488 cm2/Vs.
Liposomal drug delivery products have been already commercialized in tumor therapeutics, which can realize passive tumor targeting via enhanced permeability and retention (EPR) effect resulting from the leaky tumor vasculature. To control drug release out of the liposomes, thermo-sensitive liposomes (TSLs) have been developed so that an abrupt exposure of highly concentrated drugs to tumor tissues was enabled by locally treated thermal stimuli. As interests upon TSL have increased along with ongoing clinical trials, some types of TSLs with different physical properties in pharmacokinetics and the mechanism of drug release have been formulated. However, there are few protocols established with a desirable heat source to maximize the efficacy of different TSLs as treating tumors. In this study, we examined different protocols for the most effective application of different TSLs to tumor therapy. First, we examined if enhancing the accumulation of TSLs within tumor tissues prior to bursting drugs out of TSLs could lead to increasing anti-tumor efficacy. Second, we compared the efficiency of two different heat sources on the use of TSL, a warm water bath (42°C) and high intensity focused ultrasound (HIFU). Our study suggests that the specified protocol be setup for TSLs with different physical properties to optimally function in tumor therapies.
Data on the prevalence of intracranial aneurysms in the general population come from autopsy and from angiography series. A recent review found that the prevalence of intracranial aneurysms for adults without a history of subarachnoid hemorrhage (SAH) is approximately 2%, with a male to female ratio of approximately 1 to 1.3. The same analysis found that the prevalence of aneurysms increases with age, peaking in the 69–79 year age group. Nearly half of all intracranial aneurysms become symptomatic during the patient's lifetime, usually presenting as subarachnoid hemorrhage. In North America, approximately 28,000 cases of aneurysmal SAH occur each year, mostly in adults.
As opposed to fusiform aneurysms, which are encountered in the extracranial peripheral vasculature, intracranial aneurysms are typically saccular in morphology. Intracranial aneurysms possess a well-defined neck and sac distinct from the lumen of the parent vessel and are frequently located at proximal intracranial arterial branching points. Although the pathophysiology of intracranial aneurysms is controversial, they are thought to arise from defects (congenital or acquired) in the muscularis media. Once an aneurysm has developed, conditions such as hypertension and tobacco smoking will likely increase the risk of rupture, leading to SAH. Certain conditions (e.g., autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome type IV, Alpha-1 Antitrypsin Deficiency (A-1ATD)) are associated with the formation of cerebral aneurysms, presumably from the predisposition for the development of focal weak spots in vessel walls near arterial branch points.
Fed-batch operations are semi-batch operations in which one or more streams of feed containing nutrient sources, precursors, inducers, and mineral sources are fed either continuously or intermittently during the course of otherwise batch operations. The culture content is harvested either fully or partially at the end of the run and is used as the inoculum for the next cycle. By regulating the feed rates, it is possible to regulate the bioreactor environment to maximize the total rate of production, the reactor productivity, or the product yield.
Many industrially important bioreactor operations involving microbial and animal cells are carried out in fed-batch mode. These so-called fed-batch cultures have been found to be particularly effective for fermentation processes and cell cultures in which it is desirable to overcome such common phenomena as substrate inhibition, catabolite repression, product inhibition, and glucose effects to achieve high cell density for efficient fermentation, to minimize high viscosity effects, and to take advantage of auxotrophic mutants. Products produced by fed-batch cultures include amino acids, antibiotics, enzymes, microbial cells, organic chemicals, polysaccharides, proteins, tissue culture products, and various recombinant DNA products.
In previous chapters on optimization, we saw that once a process model in the form of mass balance equations is developed, it can be optimized using, among other methods, Pontryagin's maximum principle (PMP), or when a statistical model such as a neural network model is available, it can be optimized using a method of optimization that is most appropriate for the model.
As discussed in Chapter 4, various physical and chemical phenomena favor fed-batch operations. For physical reasons, such as the need to use auxotrophic mutants, attainment of high cell and metabolite concentrations, and alleviation of high viscosity, the use of fed-batch is obvious and intuitive, whereas for chemical reasons, such as substrate inhibition, glucose effects, and catabolite repressions, the use of fed-batch operation requires recognition of nonmonotonic specific rates such as cell growth, substrate consumption, and product formation, μ, σ, and π. In other words, at least one of the specific rates must exhibit a maximum with respect to the substrate concentration.
In this chapter, we consider simple chemical reactions in idealized reactors. Simplicity of such systems helps us understand more complex microbial reactions. With the brief description of each type of idealized reactor operation presented in Chapter 2, we consider now the simplest case of maximizing the reaction rate of a single isothermal reaction in a single reactor. This will be followed by the problem of maximizing the reaction rate using two reactors. Finally, the problem of maximizing the reaction rate of a single reaction by a single reactor with an inlet stream and an outlet stream is considered. This procedure leads naturally to the concept of fed-batch operation, a form of semi-batch operation in which there is only an inlet stream. The simplest fermentation, growing of microbial cells on a single limiting substrate, is used to illustrate the concept of fed-batch culture.
The primary objective of optimization of chemical and biochemical reactions is to maximize the reaction rate and/or yield (selectivity). For single reactions, maximization of the product formation rate or substrate consumption rate leads to the minimum reactor size or maximum productivity for a given reactor size. The minimum reactor size leads to minimum investment costs, and maximum productivity results in minimum maintenance costs. For multiple reactions, maximization of the product yield results in a minimum raw material cost, and maximization of the reaction rate leads to a minimum reactor size or a maximum productivity for a given reactor size.
When it is possible to write a complete set of mass and energy balance equations with kinetics and perhaps mass transfer rates, that is, specific rates of cell growth, product formation, formation of intermediates, and substrate consumption and mass transfer coefficients, it is possible to develop a model with a number of process parameters. Then, appropriate experimental data are generated and used to estimate the parameters in the model. However, there are many situations in which it is not possible to write a complete set of mass and energy balance equations due to lack of knowledge and understanding, for example, tissue cultures that are too complex and a lack of knowledge to be able to provide an adequate description with a limited number of balance equations. Effects of medium components on the outcome of fermentation are not well known theoretically, and therefore, empirical approaches have been used. A number of approaches can be adapted for dynamic as well as static relationships. We shall consider these approaches.
In certain situations, it is not possible to measure all state variables that describe the process. Some of the state variables cannot be readily measured or are difficult to measure in the time span necessary. Therefore, we need a method of estimating not only the parameters but also some of the difficult-to-measure state variables.
A number of items need to be considered before getting into a formal optimization. We must decide what to optimize. Here we shall call the objective function the performance index we wish to maximize, and we will maximize the performance index. When the objective is to minimize rather than maximize, such as the minimum time to achieve a desired concentration, one would change the sign of the performance index (from positive to negative) and maximize it instead. Next is the question of what would be the best initial conditions and whether the final conditions should be left unspecified or specified. There is the question of what input (control) variables we should manipulate to maximize the chosen performance index. Finally, there are questions regarding physical constraints on the manipulated variable as well as the state variables. We shall look at these questions.
One of the primary objectives of reaction engineering is to maximize the rate of formation of the product (productivity) and/or the yield (selectivity or relative yield). For an existing plant, a faster product formation rate implies a higher productivity or a corresponding reduction in plant operating time and operating cost. The increased rate implies a smaller reactor and therefore a lower capital investment cost for new plants to be built. Likewise, an improved yield implies lower raw material costs for existing and new plants. One may wish to maximize the total amount of product produced per cycle of fed-batch operation or maximize the productivity, the amount of product produced per cycle per unit operating time.
The equation-based models presented in Chapter 6 require specific rates of cell growth, substrate consumption, intermediate formation, and product formation. In this chapter, we will review the traditional methods of determining these specific rates and present a method of determining without taking time derivatives the net specific rates utilizing fed-batch cultures. Traditional methods of generating experimental data involve using primarily shake flasks (batch reactors) and, secondarily, continuous flow reactors. A new method utilizes fed-batch cultures with constant feed rates and does not require differentiation of experimental data.
It is best to generate experimental data using the type of operation that is being contemplated; that is, if a batch culture is the ultimate mode of operation, it is best to generate specific rate data using batch cultures, and if a fed-batch operation is to be used, then it is best to use fed-batch operation to generate specific rate data. Compared to chemical reactions, microbial kinetics are complex and time variant so that frequently, rate data obtained at steady state operations may not apply well to dynamic operations.