The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child

THE APPLICATION OF SPEED READING AT INTERMEDIATE LEVEL (A Case Study of Qualitative Research in One of Senior High School at Majalengka)

Muhammad Salim Pajri. 14111330143. THE APPLICATION OF SPEED READING AT INTERMEDIATE LEVEL (A Case Study of Qualitative Research in One of Senior High School at Majalengka) Reading is the important things in education, because people can get knowledge and information from reading. Without reading people cannot absorb many sciences. Here, the researcher use speed reading technique as the tool of analyzing to know the learning and teaching process at intermediate level. Moreover, the aims of this research are (1). To know the teaching and learning process of speed reading. (2). To know students’ attitude towards teaching and learning speed reading. (3). To know overcome of the difficulties of speed reading. Theoretically, is regarding to the reading area, especially in the reading comprehension by using speed reading technique. Practically, the researcher will analyze of speed reading in one of Senior High School at Majalengka which has benefit for teacher to know students’ ability in school. The research finding and discussion told about the teaching and learning process of speed reading at intermediate level. There are three activities of speed reading techniques. (1) Preparation Activity: teacher begins with greetings, deliver material and prepare students by warming up to focuss in learning process. (2) Core Activity: teacher teaches all the materials of speed reading. (3) Follow-up Activity: teacher gives exercise as the activity to know students score of speed reading test. The result of the analysis shows there are 5 students’ attitude towards teaching and learning speed reading. then, the finding shows that (1). Students’ feeling towards teaching and learning using speed reading in general: students like speed reading then also comfortable. (2). Students’ feeling towards the process of teaching and learning speed reading: they get comprehension of this technique. (3). Students’ difficulties in learning using speed reading: there are unfamiliar word on athe text. (4). Students’ feeling towards their comprehension in learning using speed reading: they get purpose in speed reading learning. (5). Students’ motivation in learning using speed reading: they can read books in fast time. It was found the overcome of difficulties of speed reading technique they are the process of the teaching speed reading and response the students’ response towards it, difficulties, disadvantages and teaching using speed reading technique and the result, usefulness, critics, and suggestions of teaching using speed reading technique. From the research that has been done, it can be concluded that there is way to apply speed reading by using steps of speed reading. From this technique will increase students’ ability in reading process. It can help students to read fast and efficient time. Keywords: Reading Comprehension, Speed Reading, Intermediate Leve

Struggles over access to the Muslim public sphere: Multiple publics and discourses on agency, belonging and citizenship (Introduction to the Themed Section)

Abstract This introductory essay provides the context for the articles in this Themed Section. Despite the diversity in locations, historical backgrounds and contemporary processes of change, all contributors to this Themed Section focus on the struggle of Muslim groups over access to an emergent Muslim public sphere. They highlight the contestations of and shifts in the notions of agency, belonging, and citizenship in nation-states with Muslim communities within its borders. The introduction consists of two parts. The first part reviews the notion of the public sphere as conceptualized by Habermas and critiqued by scholars of a diversity of backgrounds. In relation to the concept of the Muslim public sphere, three aspects of critique are given closer c

Laboratory selection for an accelerated mosquito sexual development rate

<p>Abstract</p> <p>Background</p> <p>Separating males and females at the early adult stage did not ensure the virginity of females of <it>Anopheles arabiensis </it>(Dongola laboratory strain), whereas two years earlier this method had been successful. In most mosquito species, newly emerged males and females are not able to mate successfully. For anopheline species, a period of 24 h post-emergence is generally required for the completion of sexual maturation, which in males includes a 180° rotation of the genitalia. In this study, the possibility of an unusually shortened sexual maturity period in the laboratory-reared colony was investigated.</p> <p>Methods</p> <p>The effect of two different sex-separation methods on the virginity of females was tested: females separated as pupae or less than 16 h post-emergence were mated with males subjected to various doses of radiation. T-tests were performed to compare the two sex-separation methods. The rate of genitalia rotation was compared for laboratory-reared and wild males collected as pupae in Dongola, Sudan, and analysed by Z-tests. Spermatheca dissections were performed on females mated with laboratory-reared males to determine their insemination status.</p> <p>Results</p> <p>When the sex-separation was performed when adults were less than 16 h post-emergence, expected sterility was never reached for females mated with radio-sterilized males. Expected sterility was accomplished only when sexes were separated at the pupal stage. Observation of genitalia rotation showed that some males from the laboratory strain Dongola were able to successfully mate only 11 h after emergence and 42% of the males had already completed rotation. A small proportion of the same age females were inseminated. Wild males showed a much slower genitalia rotation rate. At 17 h post-emergence, 96% of the laboratory-reared males had completed genitalia rotation whereas none of the wild males had.</p> <p>Conclusion</p> <p>This colony has been cultured in the laboratory for over one hundred generations, and now has accelerated sexual maturation when compared with the wild strain. This outcome demonstrates the kinds of selection that can be expected during insect colonization and maintenance, particularly when generations are non-overlapping and similar-age males must compete for mates.</p

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

(c) The Author/sCarriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.Published onlin

An overview of animal prion diseases

Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC). Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases