Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions

The slow progression of early AMD stages to advanced AMD requires the use of surrogate endpoints in clinical trials. The use of combined endpoints may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite endpoints as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite endpoints used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite endpoint categories were: Combined structural and functional endpoints, combined structural endpoints, combined functional endpoints and combined multi-categorical endpoints. The majority of the studies included binary composite endpoints. There was a lack of sensitivity analyses of different endpoints against accepted outcomes (i.e. progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined endpoints in clinical studies of early stages of AMD exists and no surrogate endpoints have been accepted for AMD progression

Sperm parameters and epididymis function in transgenic rats overexpressing the Ca-2-binding protein regucalcin: a hidden role for Ca-2 in sperm maturation?

Sperm undergo maturation acquiring progressive motility and the ability to fertilize oocytes through exposure to the components of the epididymal fluid (EF). Although the establishment of a calcium (Ca-2) gradient along the epididymis has been described, its direct effects on epididymal function remain poorly explored. Regucalcin (RGN) is a Ca-2-binding protein, regulating the activity of Ca-2-channels and Ca-2-ATPase, for which a role in male reproductive function has been suggested. This study aimed at comparing the morphology, assessed by histological analysis, and function of epididymis, by analysis of sperm parameters, antioxidant potential and Ca-2 fluxes, between transgenic rats overexpressing RGN (Tg-RGN) and their wild-type littermates. Tg-RGN animals displayed an altered morphology of epididymis and lower sperm counts and motility. Tissue incubation with Ca-45(2) showed also that epididymis of Tg-RGN displayed a diminished rate of Ca-2-influx, indicating unbalanced Ca-2 concentrations in the epididymal lumen. Sperm viability and the frequency of normal sperm, determined by the one-step eosin-nigrosin staining technique and the Diff-Quik staining method, respectively, were higher in Tg-RGN. Moreover, sperm of Tg-RGN rats showed a diminished incidence of tail defects. Western blot analysis demonstrated the presence of RGN in EF as well as its higher expression in the corpus region. The results presented herein demonstrated the importance of maintaining Ca-2-levels in the epididymal lumen and suggest a role for RGN in sperm maturation. Overall, a new insight into the molecular mechanisms driving epididymal sperm maturation was obtained, which could be relevant to development of better approaches in male infertility treatment and contraception.Portuguese Foundation for Science and Technology (FCT) under Program COMPETE [PEst-C/SAU/UI0709/2011]; FCT; FCT fellowships [SFRH/BD/60945/2009, SRFH/BPD/80451/2011]info:eu-repo/semantics/publishedVersio

Large Scale CW ECRH Systems : Some considerations

Electron Cyclotron Resonance Heating (ECRH) is a key component in the heating arsenal for the next step fusion devices like W7-X and ITER. These devices are equipped with superconducting coils and are designed to operate steady state. ECRH must thus operate in CW-mode with a large flexibility to comply with various physics demands such as plasma start-up, heating and current drive, as well as configurationand MHD - control. The request for many different sophisticated applications results in a growing complexity, which is in conflict with the request for high availability, reliability, and maintainability. ‘Advanced’ ECRH-systems must, therefore, comply with both the complex physics demands and operational robustness and reliability. The W7-X ECRH system is the first CW- facility of an ITER relevant size and is used as a test bed for advanced components. Proposals for future developments are presented together with improvements of gyrotrons, transmission components and launchers

Physical activity in pregnancy: a qualitative study of the beliefs of overweight and obese pregnant women

<p>Abstract</p> <p>Background</p> <p>Whilst there has been increasing research interest in interventions which promote physical activity during pregnancy few studies have yielded detailed insights into the views and experiences of overweight and obese pregnant women themselves. The qualitative study described in this paper aimed to: (i) explore the views and experiences of overweight and obese pregnant women; and (ii) inform interventions which could promote the adoption of physical activity during pregnancy.</p> <p>Methods</p> <p>The study was framed by a combined Subtle Realism and Theory of Planned Behaviour (TPB) approach. This enabled us to examine the hypothetical pathway between beliefs and physical activity intentions within the context of day to day life. The study sample for the qualitative study was chosen by stratified, purposive sampling from a previous study of physical activity measurements in pregnancy. Research participants for the current study were recruited on the basis of Body Mass Index (BMI) at booking and parity. Semi-structured, in-depth interviews were conducted with 14 overweight and obese pregnant women. Data analysis was undertaken using a Framework Approach and was informed by TPB.</p> <p>Results</p> <p>Healthy eating was often viewed as being of greater importance for the health of mother and baby than participation in physical activity. A commonly cited motivator for maintaining physical activity during pregnancy is an aid to reducing pregnancy-related weight gain. However, participants often described how they would wait until the postnatal period to try and lose weight. A wide range of barriers to physical activity during pregnancy were highlighted including both internal (physical and psychological) and external (work, family, time and environmental). The study participants also lacked access to consistent information, advice and support on the benefits of physical activity during pregnancy.</p> <p>Conclusions</p> <p>Interventions to encourage recommended levels of physical activity in pregnancy should be accompanied by accessible and consistent information about the positive effects for mother and baby. More research is required to examine how to overcome barriers to physical activity and to understand which interventions could be most effective for overweight/obese pregnant women. Midwives should be encouraged to do more to promote activity in pregnancy.</p

Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study

BACKGROUND: Recruiting asymptomatic participants with early disease stages into studies is challenging and only little is known about facilitators and barriers to screening and recruitment of study participants. Thus we assessed factors associated with screening rates in the MACUSTAR study, a multi-centre, low-interventional cohort study of early stages of age-related macular degeneration (AMD). METHODS: Screening rates per clinical site and per week were compiled and applicable recruitment factors were assigned to respective time periods. A generalized linear mixed-effects model including the most relevant recruitment factors identified via in-depth interviews with study personnel was fitted to the screening data. Only participants with intermediate AMD were considered. RESULTS: A total of 766 individual screenings within 87 weeks were available for analysis. The mean screening rate was 0.6 ± 0.9 screenings per week among all sites. The participation at investigator teleconferences (relative risk increase 1.466, 95% CI [1.018-2.112]), public holidays (relative risk decrease 0.466, 95% CI [0.367-0.591]) and reaching 80% of the site's recruitment target (relative risk decrease 0.699, 95% CI [0.367-0.591]) were associated with the number of screenings at an individual site level. CONCLUSIONS: Careful planning of screening activities is necessary when recruiting early disease stages in multi-centre observational or low-interventional studies. Conducting teleconferences with local investigators can increase screening rates. When planning recruitment, seasonal and saturation effects at clinical site level need to be taken into account. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017

Agreement between pedometer and accelerometer in measuring physical activity in overweight and obese pregnant women

<p>Abstract</p> <p>Background</p> <p>Inexpensive, reliable objective methods are needed to measure physical activity (PA) in large scale trials. This study compared the number of pedometer step counts with accelerometer data in pregnant women in free-living conditions to assess agreement between these measures.</p> <p>Methods</p> <p>Pregnant women (n = 58) with body mass index ≥25 kg/m²at median 13 weeks' gestation wore a GT1M Actigraph accelerometer and a Yamax Digi-Walker CW-701 pedometer for four consecutive days. The Spearman rank correlation coefficients were determined between pedometer step counts and various accelerometer measures of PA. Total agreement between accelerometer and pedometer step counts was evaluated by determining the 95% limits of agreement estimated using a regression-based method. Agreement between the monitors in categorising participants as active or inactive was assessed by determining Kappa.</p> <p>Results</p> <p>Pedometer step counts correlated moderately (r = 0.36 to 0.54) with most accelerometer measures of PA. Overall step counts recorded by the pedometer and the accelerometer were not significantly different (medians 5961 vs. 5687 steps/day, p = 0.37). However, the 95% limits of agreement ranged from -2690 to 2656 steps/day for the mean step count value (6026 steps/day) and changed substantially over the range of values. Agreement between the monitors in categorising participants to active and inactive varied from moderate to good depending on the criteria adopted.</p> <p>Conclusions</p> <p>Despite statistically significant correlations and similar median step counts, the overall agreement between pedometer and accelerometer step counts was poor and varied with activity level. Pedometer and accelerometer steps cannot be used interchangeably in overweight and obese pregnant women.</p

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility