Evaluating parameters affecting drug fate at the intramuscular injection site

Intramuscular (IM) injections are a well-established method of delivering a variety of therapeutics formulated for parenteral administration. While the wide range of commercial IM pharmaceuticals provide a wealth of pharmacokinetic (PK) information following injection, there remains an inadequate understanding of drug fate at the IM injection site that could dictate these PK outcomes. An improved understanding of injection site events could improve approaches taken by formulation scientists to identify therapeutically effective and consistent drug PK outcomes. Interplay between the typically non-physiological aspects of drug formulations and the homeostatic IM environment may provide insights into the fate of drugs at the IM injection site, leading to predictions of how a drug will behave post-injection in vivo. Immune responses occur by design after e.g. vaccine administration, however immune responses post-injection are not in the scope of this article. Taking cues from existing in vitro modelling technologies, the purpose of this article is to propose “critical parameters” of the IM environment that could be examined in hypothesis-driven studies. Outcomes of such studies might ultimately be useful in predicting and improving in vivo PK performance of IM injected drugs

Evaluating parameters affecting drug fate at the intramuscular injection site

Intramuscular (IM) injections are a well-established method of delivering a variety of therapeutics formulated for parenteral administration. While the wide range of commercial IM pharmaceuticals provide a wealth of pharmacokinetic (PK) information following injection, there remains an inadequate understanding of drug fate at the IM injection site that could dictate these PK outcomes. An improved understanding of injection site events could improve approaches taken by formulation scientists to identify therapeutically effective and consistent drug PK outcomes. Interplay between the typically non-physiological aspects of drug formulations and the homeostatic IM environment may provide insights into the fate of drugs at the IM injection site, leading to predictions of how a drug will behave post-injection in vivo. Immune responses occur by design after e.g. vaccine administration, however immune responses post-injection are not in the scope of this article. Taking cues from existing in vitro modelling technologies, the purpose of this article is to propose “critical parameters” of the IM environment that could be examined in hypothesis-driven studies. Outcomes of such studies might ultimately be useful in predicting and improving in vivo PK performance of IM injected drugs

Macular pigment optical density and photophobia light threshold

AbstractLight absorption by macular pigment may attenuate visual discomfort, or photophobia, for targets composed of short-wavelength light. Macular pigment optical density (MPOD) and photophobia light thresholds were measured psychophysically in 10 subjects. The energy necessary to induce photophobia for a short-wavelength target relative to a long-wavelength target was linearly related to MPOD, as well as estimates of peak MPOD and integrated macular pigment. In four subjects who consumed lutein supplements, increases in MPOD corresponded to increases in photophobia light thresholds. Light absorption by macular pigment appears to influence the amount of short-wavelength light necessary to elicit photophobia

Time cost associated with sports participation for athletes with high support needs : A time-motion analysis of tasks required for para swimming

Objectives People with cerebral palsy and high support needs (CP&HSN) are profoundly inactive but also under-represented in studies evaluating physical activity interventions. Reasons for their exclusion have not been evaluated. We hypothesised that CP&HSN would be associated with high time costs of preparatory activities (eg, getting dressed/undressed), possibly contributing to low participation and under-representation. Accordingly, this pilot study aimed to: (1) evaluate whether the time required for preparatory activities was extremely different (≥3 SD) between swimmers with and without CP&HSN; and (2) provide a qualitative indication of the preparatory tasks undertaken by swimmers with CP&HSN. Methods Each of three experienced (5 years) para swimmers with CP&HSN and 20 non-disabled swimmers were timed entering and then exiting the pool on three occasions. Mean entry and exit time for each para swimmer was compared with the group mean for non-disabled swimmers, and differences of greater than 3.0 SD were considered extreme. A qualitative description of the tasks completed by the para swimmers was recorded. Results The differences in time costs between para and non-disabled swimmers met the criterion of extreme. Pool entry times for para swimmers were 8–13 times greater (Effect size = 4.1–8.7). Pool exit times were 6–10 times greater (ES=7.0–9.5). 90% of tasks completed by para swimmers required personal assistance or wheeled mobility. Conclusions This pilot study suggests that, compared with non-disabled swimmers, time costs for preparation to commence or depart training are extremely high for swimmers with CP&HSN. Further research is required to evaluate the veracity of these findings

Automatic memory processes in normal ageing and Alzheimer’s disease

This study examined the contribution of automatic and controlled uses of memory to stem completion in young, middle-aged and older adults, and compared these data with a study involving patients with Alzheimer’s disease (AD) who performed the same task (Hudson and Robertson, 2007). In an inclusion task participants aimed to complete three-letter word stems with a previously studied word, in an exclusion task the aim was to avoid using studied words to complete stems. Performances under inclusion and exclusion conditions were contrasted to obtain estimates of controlled and automatic memory processes using process-dissociation calculations (Jacoby, 1991). An age-related decline, evident from middle age was observed for the estimate of controlled processing, whereas the estimate of automatic processing remained invariant across the age groups. This pattern stands in contrast to what is observed in AD, where both controlled and automatic processes have been shown to be impaired. Therefore, the impairment in memory processing on stem completion that is found in AD is qualitatively different from that observed in normal ageing

Measuring white matter microstructure in 1,457 cannabis users and 1,441 controls : A systematic review of diffusion-weighted MRI studies

Introduction: Cannabis is the most widely used regulated substance by youth and adults. Cannabis use has been associated with psychosocial problems, which have been partly ascribed to neurobiological changes. Emerging evidence to date from diffusion-MRI studies shows that cannabis users compared to controls show poorer integrity of white matter fibre tracts, which structurally connect distinct brain regions to facilitate neural communication. However, the most recent evidence from diffusion-MRI studies thus far has yet to be integrated. Therefore, it is unclear if white matter differences in cannabis users are evident consistently in selected locations, in specific diffusion-MRI metrics, and whether these differences in metrics are associated with cannabis exposure levels. Methods: We systematically reviewed the results from diffusion-MRI imaging studies that compared white matter differences between cannabis users and controls. We also examined the associations between cannabis exposure and other behavioral variables due to changes in white matter. Our review was pre-registered in PROSPERO (ID: 258250; https://www.crd.york.ac.uk/prospero/). Results: We identified 30 diffusion-MRI studies including 1,457 cannabis users and 1,441 controls aged 16-to-45 years. All but 6 studies reported group differences in white matter integrity. The most consistent differences between cannabis users and controls were lower fractional anisotropy within the arcuate/superior longitudinal fasciculus (7 studies), and lower fractional anisotropy of the corpus callosum (6 studies) as well as higher mean diffusivity and trace (4 studies). Differences in fractional anisotropy were associated with cannabis use onset (4 studies), especially in the corpus callosum (3 studies). Discussion: The mechanisms underscoring white matter differences are unclear, and they may include effects of cannabis use onset during youth, neurotoxic effects or neuro adaptations from regular exposure to tetrahydrocannabinol (THC), which exerts its effects by binding to brain receptors, or a neurobiological vulnerability predating the onset of cannabis use. Future multimodal neuroimaging studies, including recently developed advanced diffusion-MRI metrics, can be used to track cannabis users over time and to define with precision when and which region of the brain the white matter changes commence in youth cannabis users, and whether cessation of use recovers white matter differences. Systematic review registration: www.crd.york.ac.uk/prospero/, identifier: 258250

Variant-specific inflation factors for assessing population stratification at the phenotypic variance level

In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term \u27variance stratification\u27. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI

Noncommutative homogeneous spaces: the matrix case

Given a quantum subgroup $G\subset U_n$ and a number $k\leq n$ we can form the homogeneous space $X=G/(G\cap U_k)$, and it follows from the Stone-Weierstrass theorem that $C(X)$ is the algebra generated by the last $n-k$ rows of coordinates on $G$. In the quantum group case the analogue of this basic result doesn't necessarily hold, and we discuss here its validity, notably with a complete answer in the group dual case. We focus then on the "easy quantum group" case, with the construction and study of several algebras associated to the noncommutative spaces of type $X=G/(G\cap U_k^+)$.Comment: 24 page

JACK trial protocol: a phase III multicentre cluster randomised controlled trial of a school-based relationship and sexuality education intervention focusing on young male perspectives.

INTRODUCTION: Teenage pregnancy remains a worldwide health concern which is an outcome of, and contributor to, health inequalities. The need for gender-aware interventions with a focus on males in addressing teenage pregnancy has been highlighted as a global health need by WHO and identified in systematic reviews of (relationship and sexuality education (RSE)). This study aims to test the effectiveness of an interactive film-based RSE intervention, which draws explicit attention to the role of males in preventing an unintended pregnancy by reducing unprotected heterosexual teenage sex among males and females under age 16 years. METHODS AND ANALYSIS: A phase III cluster randomised trial with embedded process and economic evaluations. If I Were Jack encompasses a culturally sensitive interactive film, classroom materials, a teacher-trainer session and parent animations and will be delivered to replace some of the usual RSE for the target age group in schools in the intervention group. Schools in the control group will not receive the intervention and will continue with usual RSE. Participants will not be blinded to allocation. Schools are the unit of randomisation stratified per country and socioeconomic status. We aim to recruit 66 UK schools (24 in Northern Ireland; 14 in each of England, Scotland and Wales), including approximately 7900 pupils. A questionnaire will be administered at baseline and at 12-14 months postintervention. The primary outcome is reported unprotected sex, a surrogate measure associated with unintended teenage pregnancy. Secondary outcomes include knowledge, attitudes, skills and intentions relating to avoiding teenage pregnancy in addition to frequency of engagement in sexual intercourse, contraception use and diagnosis of sexually transmitted infections. ETHICS AND DISSEMINATION: Ethical approval was obtained from Queen's University Belfast. Results will be published in peer-reviewed journals and disseminated to stakeholders. Funding is from the National Institute for Health Research. TRIAL REGISTRATION NUMBER: ISRCTN99459996