Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Nucleoside Azide-Alkyne Cycloaddition Reactions Under Solvothermal Conditions or Using Copper Vials in a Ball Mill

Novel nucleoside analogues containing photoswitchable moieties were prepared using 'click' cycloaddition reactions between 5 '-azido-5 '-deoxythymidine and mono- or bis-N-propargylamide-substituted azobenzenes. In solution, high to quantitative yields were achieved using 5mol% Cu(I) in the presence of a stabilizing ligand. 'Click' reactions using the monopropargylamides were also effected in the absence of added cuprous salts by the application of liquid assisted grinding (LAG) in metallic copper reaction vials. Specifically, high speed vibration ball milling (HSVBM) using a 3/32('') (2.38mm) diameter copper ball (62mg) at 60Hz overnight in the presence of ethyl acetate lead to complete consumption of the 5 '-azido nucleoside with clean conversion to the corresponding 1,3-triazole.

Immunological determination of the pharmaceutical diclofenac in environmental and biological samples

A highly sensitive and specific competitive ELISA on 96-microwell plates was developed for the analysis of the nonsteroidal anti-inflammatory drug diclofenac. Within the water cycle in Europe, this is one of the most frequently detected pharmaceutically active compounds. The LOD at a signal-tonoise ratio (S/N) of 3, and the IC ₅₀, were found to be 6 ng/L and 60 ng/L respectively in tap water. In a comparative study using ELISA and GC-MS, diclofenac levels in wastewater from 21 sewage treatment plants were determined and a good correlation between these methods was found (ELISA vs. GCMS: r = 0.70, slope = 0,90, intercept = 0.37, n = 24). An average degradation rate of -25% can be calculated. Labscale-experiments on the elimination of diclofenac in continuous pilot sewage plants revealed a removal rate of only 5% over a period of 13 weeks. In a further study, the ELISA was applied to a number of extracts of various animal tissues from a range of species, and again a very good relationship between ELISA and LC-ESI/MS data sets was obtained (r = 0.90, p<0.0001; n = 117). The ELISA has proven to be a simple, rapid, reliable and affordable alternative to otherwise costly and advanced techniques for the detection of diclofenac in matrix diverse water samples and tissue extracts after only relatively simple sample preparation. © 2007 American Chemical Society.

Is the Schwabe organ a retained larval eye? Anatomical and behavioural studies of a novel sense organ in adult leptochiton asellus (Mollusca, Polyplacophora) indicate links to larval photoreceptors

The discovery of a sensory organ, the Schwabe organ, was recently reported as a unifying feature of chitons in the order Lepidopleurida. It is a patch of pigmented tissue located on the roof of the pallial cavity, beneath the velum on either side of the mouth. The epithelium is densely innervated and contains two types of potential sensory cells. As the function of the Schwabe organ remains unknown, we have taken a cross-disciplinary approach, using anatomical, histological and behavioural techniques to understand it. In general, the pigmentation that characterises this sensory structure gradually fades after death; however, one particular concentrated pigment dot persists. This dot is positionally homologous to the larval eye in chiton trochophores, found in the same neuroanatomical location, and furthermore the metamorphic migration of the larval eye is ventral in species known to possess Schwabe organs. Here we report the presence of a discrete subsurface epithelial structure in the region of the Schwabe organ in Leptochiton asellus that histologically resembles the chiton larval eye. Behavioural experiments demonstrate that Leptochiton asellus with intact Schwabe organs actively avoid an upwelling light source, while Leptochiton asellus with surgically ablated Schwabe organs and a control species lacking the organ (members of the other extant order, Chitonida) do not (Kruskal-Wallis, H = 24.82, df = 3, p < 0.0001). We propose that the Schwabe organ represents the adult expression of the chiton larval eye, being retained and elaborated in adult lepidopleurans.

Determinants and two-year change in anterior chamber angle width in a Chinese population

Objective: To study the population distribution and longitudinal changes in anterior chamber angle width and its determinants among Chinese adults. Design: Prospective cohort, population-based study. Participants: Persons aged 35 years or more residing in Guangzhou, China, who had not previously undergone incisional or laser eye surgery. Methods: In December 2008 and December 2010, all subjects underwent automated keratometry, and a random 50% sample had anterior segment optical coherence tomography with measurement of angle-opening distance at 500 μm (AOD500), angle recess area (ARA), iris thickness at 750 μm (IT750), iris curvature, pupil diameter, corneal thickness, anterior chamber width (ACW), lens vault (LV), and lens thickness (LT) and measurement of axial length (AL) and anterior chamber depth (ACD) by partial coherence laser interferometry. Main Outcome Measures: Baseline and 2-year change in AOD500 and ARA in the right eye. Results: A total of 745 subjects were present for full biometric testing in both 2008 and 2010 (mean age at baseline, 52.2 years; standard deviation [SD], 11.5 years; 53.7% were female). Test completion rates in 2010 varied from 77.3% (AOD500: 576/745) to 100% (AL). Mean AOD500 decreased from 0.25 mm (SD, 0.13 mm) in 2008 to 0.21 mm (SD, 13 mm) in 2010 (difference, -0.04; 95% confidence interval [CI], -0.05 to -0.03). The ARA decreased from 21.5±3.73 10^-2 mm² to 21.0±3.64 10 ^-2 mm² (difference, -0.46; 95% CI, -0.52 to -0.41). The decrease in both was most pronounced among younger subjects and those with baseline AOD500 in the widest quartile at baseline. The following baseline variables were significantly associated with a greater 2-year decrease in both AOD500 and ARA: deeper ACD, steeper iris curvature, smaller LV, greater ARA, and greater AOD500. By using simple regression models, we could explain 52% to 58% and 93% of variation in baseline AOD500 and ARA, respectively, but only 27% and 16% of variation in 2-year change in AOD500 and ARA, respectively. Conclusions: Younger persons and those with the least crowded anterior chambers at baseline have the largest 2-year decreases in AOD500 and ARA. The ability to predict change in angle width based on demographic and biometric factors is relatively poor, which may have implications for screening. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2012 American Academy of Ophthalmology.

Visual symptoms and retinal straylight after laser peripheral iridotomy: the Zhongshan Angle-Closure Prevention Trial.

OBJECTIVE: To assess the impact of laser peripheral iridotomy (LPI) on forward-scatter of light and subjective visual symptoms and to identify LPI parameters influencing these phenomena. DESIGN: Cohort study derived from a randomized trial, using an external control group. PARTICIPANTS: Chinese subjects initially aged 50 or older and 70 years or younger with bilateral narrow angles undergoing LPI in 1 eye selected at random, and age- and gender-matched controls. METHODS: Eighteen months after laser, LPI-treated subjects underwent digital iris photography and photogrammetry to characterize the size and location of the LPI, Lens Opacity Classification System III cataract grading, and measurement of retinal straylight (C-Quant; OCULUS, Wetzlar, Germany) in the treated and untreated eyes and completed a visual symptoms questionnaire. Controls answered the questionnaire and underwent straylight measurement and (in a random one-sixth sample) cataract grading. MAIN OUTCOME MEASURES: Retinal straylight levels and subjective visual symptoms. RESULTS: Among 230 LPI-treated subjects (121 [58.8%] with LPI totally covered by the lid, 43 [19.8%] with LPI partly covered by the lid, 53 [24.4%] with LPI uncovered by the lid), 217 (94.3%) completed all testing, as did 250 (93.3%) of 268 controls. Age, gender, and prevalence of visual symptoms did not differ between treated subjects and controls, although nuclear (P<0.01) and cortical (P = 0.03) cataract were less common among controls. Neither presenting visual acuity nor straylight score differed between the treated and untreated eyes among all treated persons, nor among those (n = 96) with LPI partially or totally uncovered. Prevalence of subjective glare did not differ significantly between participants with totally covered LPI (6.61%; 95% confidence interval [CI], 3.39%-12.5%), partially covered LPI (11.6%; 95% CI, 5.07%-24.5%), or totally uncovered LPI (9.43%; 95% CI, 4.10%-10.3%). In regression models, only worse cortical cataract grade (P = 0.01) was associated significantly with straylight score, and no predictors were associated with subjective glare. None of the LPI size or location parameters were associated with straylight or subjective symptoms. CONCLUSIONS: These results suggests that LPI is safe regarding measures of straylight and visual symptoms. This randomized design provides strong evidence that treatment programs for narrow angles would be unlikely to result in important medium-term visual disability.

A proposed simple method for measurement in the anterior chamber angle: biometric gonioscopy

OBJECTIVE:

To design a system of gonioscopy that will allow greater interobserver reliability and more clearly defined screening cutoffs for angle closure than current systems while being simple to teach and technologically appropriate for use in rural Asia, where the prevalence of angle-closure glaucoma is highest.

DESIGN:

Clinic-based validation and interobserver reliability trial.

PARTICIPANTS:

Study 1: 21 patients 18 years of age and older recruited from a university-based specialty glaucoma clinic; study 2: 32 patients 18 years of age and older recruited from the same clinic.

INTERVENTION:

In study 1, all participants underwent conventional gonioscopy by an experienced observer (GLS) using the Spaeth system and in the same eye also underwent Scheimpflug photography, ultrasonographic measurement of anterior chamber depth and axial length, automatic refraction, and biometric gonioscopy with measurement of the distance from iris insertion to Schwalbe's line using a reticule based in the slit-lamp ocular. In study 2, all participants underwent both conventional gonioscopy and biometric gonioscopy by an experienced gonioscopist (NGC) and a medical student with no previous training in gonioscopy (JK).

MAIN OUTCOME MEASURES:

Study 1: The association between biometric gonioscopy and conventional gonioscopy, Scheimpflug photography, and other factors known to correlate with the configuration of the angle. Study 2: Interobserver agreement using biometric gonioscopy compared to that obtained with conventional gonioscopy.

RESULTS:

In study 1, there was an independent, monotonic, statistically significant relationship between biometric gonioscopy and both Spaeth angle (P = 0.001, t test) and Spaeth insertion (P = 0.008, t test) grades. Biometric gonioscopy correctly identified six of six patients with occludable angles according to Spaeth criteria. Biometric gonioscopic grade was also significantly associated with the anterior chamber angle as measured by Scheimpflug photography (P = 0.005, t test). In study 2, the intraclass correlation coefficient between graders for biometric gonioscopy (0.97) was higher than for Spaeth angle grade (0.72) or Spaeth insertion grade (0.84).

CONCLUSION:

Biometric gonioscopy correlates well with other measures of the anterior chamber angle, shows a higher degree of interobserver reliability than conventional gonioscopy, and can readily be learned by an inexperienced observer.

Biometric gonioscopy and the effects of age, race, and sex on the anterior chamber angle.

AIM:

To utilise a novel method for making measurements in the anterior chamber in order to compare the anterior chamber angles of people of European, African, and east Asian descent aged 40 years and over.

METHODS:

A cross sectional study on 15 people of each sex from each decade from the 40s to the 70s, from each of three racial groups-black, white, and Chinese Singaporeans. Biometric gonioscopy (BG) utilises a slit lamp mounted reticule to make measurements from the apparent iris insertion to Schwalbe's line through a Goldmann one mirror goniolens. The main outcome measures were BG measurements of the anterior chamber angle as detailed above.

RESULTS:

There was no significant difference in angle measurement between black, white, and Chinese races in this study. However, at younger ages people of Chinese race appeared to have deeper angles than white or black people, whereas the angles of older Chinese were significantly narrower (p = 0.004 for the difference in slope of BG by age between Chinese and both black and white people).

CONCLUSION:

The failure to detect a difference in angle measurements between these groups was surprising, given the much higher prevalence of angle closure among Chinese. It appears that the overall apparent similarity of BG means between Chinese and Western populations may mask very different trends with age. The apparently more rapid decline in angle width measurements with age among Chinese may be due to the higher prevalence of cataract or "creeping angle closure." However, longitudinal inferences from cross sectional data are problematic, and this may represent a cohort phenomenon caused by the increasing prevalence of myopia in the younger Singaporean population.

Dark room provocative test and extent of angle closure: an anterior segment OCT study.

PURPOSE: To clarify the risk parameters measured by anterior segment optical coherence tomography (AS-OCT) for elevated intraocular pressures (IOP) provoked by the darkroom test and to provide recommendations for its clinical usage. METHODS: Subjects aged >40 years and whose peripheral anterior chambers were ≤1/4 corneal thickness were recruited. The anterior segment of the eye was imaged in sitting position and under both light and dark conditions and biometry was performed using anterior segment optical coherence tomography. The analyzed parameters were: (1) central anterior chamber depth (ACD); (2) anterior chamber width; (3) pupil diameter; (4) iris curvature; (5) lens thickness; and (6) number of meridians with closed angles (NCA). Then the darkroom test was performed and a positive provocative test result was defined as a rise in IOP ≥8 mm Hg after the test. Statistical analyses included: (1) the difference in parameters between positive and negative eyes; (2) the association between posttest IOP and the parameters; and (3) the difference in parameters between the 2 eyes in subjects with the asymmetric results. RESULTS: A total of 70 subjects were recruited. ACD (P=0.022), NCA in light (P<0.001), and NCA in dark (P<0.001) were different significantly between eyes with positive and negative results. There was a strong association between NCA in dark (r=0.755, P<0.001) and the posttest IOP. Among subjects with asymmetric results between the 2 eyes, the ACD was shallower and the lens thickness was larger in the positive eye. CONCLUSIONS: The posttest IOP is determined by the extent of functionally closed angles in the dark. The test may be useful in the early diagnosis of primary angle closure. At the same time, angle configuration should be evaluated to remove false positive result.

Comparisons of anterior segment biometry between Chinese and Caucasians using anterior segment optical coherence tomography.

PURPOSE: To compare anterior segment parameters between eyes of Chinese and Caucasians using anterior segment optical coherence tomography and to evaluate the association between these parameters and anterior chamber angle width between the two ethnic groups. METHODS: 60 Chinese and 60 Caucasians, 30 with open angles and 30 with narrow angles (defined as Shaffer grade < or =2 in > or =3 quadrants during dark room gonioscopy) in each group, were consecutively enrolled. One eye of each subject was randomly selected for imaging in a completely darkened room. Measurements, including anterior chamber depth (ACD), scleral spur-to-scleral spur distance (anterior chamber width (ACW)), anterior chamber angle width, iris convexity and iris thickness, were compared between the groups. The associations between angle opening distance and biometric measurements were evaluated with univariate and multivariate regression analyses. RESULTS: There were no differences in age, axial length, anterior chamber angle measurements, pupil diameter and iris convexity between Chinese and Caucasians in both open-angle and narrow-angle groups. However, the ACD and ACW were smaller and the iris was thicker in Chinese. In the multivariate analysis, the ACD was the most influential biometric parameter for angle opening distance in both Chinese and Caucasians. After adjusting the effects of axial length, age and sex, ACD and ACW were significantly smaller in Chinese. CONCLUSIONS: Chinese eyes had smaller ACD, smaller ACW and greater iris thickness than Caucasians. ACD was the most influential parameter in determining the angle width in both ethnic groups.

Supra-treatment threshold neonatal jaundice: Incidence in HIV-exposed compared to non-exposed neonates at Queen Elizabeth Central Hospital in Blantyre, Malawi

INTRODUCTION: Jaundice is the yellowish pigmentation of the skin, sclera, and mucous membranes resulting from bilirubin deposition. Children born to mothers with HIV are more likely to be born premature, with low birth weight, and to become septic-all risk factors for neonatal jaundice. Further, there has been a change in the prevention of mother-to-child transmission (PMTCT) of HIV guidelines from single-dose nevirapine to a six-week course, all of which theoretically put HIV-exposed newborns at greater risk of developing neonatal jaundice.

AIM: We carried out a study to determine the incidence of severe and clinical neonatal jaundice in HIV-exposed neonates admitted to the Chatinkha Nursery (CN) neonatal unit at Queen Elizabeth Central Hospital (QECH) in Blantyre.

METHODS: Over a period of four weeks, the incidence among non-exposed neonates was also determined for comparison between the two groups of infants. Clinical jaundice was defined as transcutaneous bilirubin levels greater than 5 mg/dL and severe jaundice as bilirubin levels above the age-specific treatment threshold according the QECH guidelines. Case notes of babies admitted were retrieved and information on birth date, gestational age, birth weight, HIV status of mother, type of feeding, mode of delivery, VDRL status of mother, serum bilirubin, duration of stay in CN, and outcome were extracted.

RESULTS: Of the 149 neonates who were recruited, 17 (11.4%) were HIV-exposed. One (5.88%) of the 17 HIV-exposed and 19 (14.4%) of 132 HIV-non-exposed infants developed severe jaundice requiring therapeutic intervention (p = 0.378). Eight (47%) of the HIV-exposed and 107 (81%) of the non-exposed neonates had clinical jaundice of bilirubin levels greater than 5 mg/dL (p < 0.001).

CONCLUSIONS: The study showed a significant difference in the incidence of clinical jaundice between the HIV-exposed and HIV-non-exposed neonates. Contrary to our hypothesis, however, the incidence was greater in HIV-non-exposed than in HIV-exposed infants.

Real-space grids and the Octopus code as tools for the development of new simulation approaches for electronic systems

Real-space grids are a powerful alternative for the simulation of electronic systems. One of the main advantages of the approach is the flexibility and simplicity of working directly in real space where the different fields are discretized on a grid, combined with competitive numerical performance and great potential for parallelization. These properties constitute a great advantage at the time of implementing and testing new physical models. Based on our experience with the Octopus code, in this article we discuss how the real-space approach has allowed for the recent development of new ideas for the simulation of electronic systems. Among these applications are approaches to calculate response properties, modeling of photoemission, optimal control of quantum systems, simulation of plasmonic systems, and the exact solution of the Schrödinger equation for low-dimensionality systems.

Quiet-Sun Hα Transients and Corresponding Small-scale Transition Region and Coronal Heating

Rapid blue- and redshifted excursions (RBEs and RREs) are likely to be the on-disk counterparts of Type II spicules. Recently, heating signatures from RBEs/RREs have been detected in IRIS slit-jaw images dominated by transition region (TR) lines around network patches. Additionally, signatures of Type II spicules have been observed in Atmospheric Imaging Assembly (AIA) diagnostics. The full-disk, ever-present nature of the AIA diagnostics should provide us with sufficient statistics to directly determine how important RBEs and RREs are to the heating of the TR and corona. We find, with high statistical significance, that at least 11% of the low coronal brightenings detected in a quiet-Sun region in He ii 304 Å can be attributed to either RBEs or RREs as observed in Hα, and a 6% match of Fe IX 171 Å detected events to RBEs or RREs with very similar statistics for both types of Hα features. We took a statistical approach that allows for noisy detections in the coronal channels and provides us with a lower, but statistical significant, bound. Further, we consider matches based on overlapping features in both time and space, and find strong visual indications of further correspondence between coronal events and co-evolving but non-overlapping, RBEs and RREs.

Molecular cloning and analysis of Xeroderma pigmentosum group-D (xpd) in zebrafish

Dissertação de mest., Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Univ. do Algarve, 2011

Comment réduire le gaspillage alimentaire dans l’industrie agroalimentaire au Québec?

L’objectif général de cet essai est de proposer des solutions qui facilitent la réduction du gaspillage alimentaire dans l’industrie agroalimentaire au Québec. Le gaspillage alimentaire se produit à toutes les étapes de la chaîne agroalimentaire. Les pertes économiques sont énormes. Chaque jour, des tonnes de denrées comestibles sont jetées, alors que plusieurs personnes ne mangent pas à leur faim. Le gaspillage alimentaire provoque une importante utilisation inutile de ressources naturelles et une grande pollution environnementale. L’analyse de la problématique du gaspillage alimentaire a permis de constater que ce phénomène est peu étudié au Québec. Le gouvernement québécois n’est pas assez impliqué dans la lutte au gaspillage alimentaire. Les actions gouvernementales prévues ont été retardées. Des solutions étrangères de réductions des pertes alimentaires ont été analysées pour déterminer leur pertinence pour le Québec. La belle province fait piètre figure si elle est comparée à certains États et à son homologue canadien la Nouvelle-Écosse. Les conclusions de l’essai montrent qu’une réduction efficace du gaspillage alimentaire au Québec passe par la mise en place d’actions concrètes dans les secteurs public et privé. Dans l’industrie agroalimentaire, les critères esthétiques pour les aliments et la mise au rebut des produits moins frais sont les axes d’intervention à privilégier. Dans le domaine public, la législation est le moyen priorisé pour l’atteinte des objectifs québécois en matière de détournement des résidus organiques. Les initiatives proposées à l’industrie agroalimentaire sont des options très intéressantes, car elles deviennent rapidement profitables. Il est conseillé au ministère du Développement durable, de l'Environnement et de la Lutte contre les changements climatiques d’aller de l’avant avec son projet de loi interdisant l’enfouissement des résidus putrescibles. Revenu Québec devrait changer la réglementation pour rendre le don alimentaire plus profitable pour les entreprises. La modification des champs d’application du double système de datation canadien par Santé Canada faciliterait l’interprétation de la date de péremption.