Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS):development and validation of a novel outcome measure

Background Recent randomised controlled trials (RCTs) in primary Sjogren's syndrome used the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjogren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjogren's syndrome: the Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS). Methods A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders. Findings Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjogren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p Interpretation The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjogren's syndrome. As a next step, the CRESS will require validation in a prospective RCT. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Surface chemistry versus whole-cell extracts: antifouling tests with seaweed metabolites

Development of research in the field of chemical inhibition of colonisation of seaweed surfaces has been constrained by the lack of appropriate methods for testing realistic concentrations of potentially deterrent compounds. Here we extend earlier work (de Nys et al. 1998) on the red alga Delisea pulchra to 6 other Australian seaweed species to investigate whether these methods could be used more generally in studies of natural defences against biofouling. We compared the effects of surface extracts of D. pulchra, Caulerpa filiformis, Dictyopteris acrostichoides, Dilophus marginatus, Laurencia rigida, Solieria robusta and Pterocladia capillacea on the settlement of 2 ecologically relevant fouling species, and further compared the effects of surface extracts to those of non-polar, whole-cell extracts of the 7 seaweeds. We also measured the natural biofouling cover of these seaweeds in a field survey and examined whether levels of biofouling on the seaweeds in the field are predicted by the activity of either the surface extracts or the whole-cell extracts of these species. The results from settlement tests with surface extracts at natural concentrations showed that 2 species, D. pulchra and C. filiformis, had non-polar metabolites on their surfaces in sufficient quantities to significantly inhibit settlement. These species also had significantly lower biofouling cover in the field compared to the other seaweeds. The results of the settlement tests with whole-cell extracts, however, demonstrated that all the seaweeds contain non-polar metabolites that inhibit settlement at concentrations lower than total whole tissue content and that no individual whole-cell extract was generally more inhibitory than the others. Therefore, we conclude that results from settlement assays with whole-cell extracts are poor predictors of natural antifouling roles of seaweed metabolites, and that such bioassays are of little use if the objective is to explore the chemical mediation of interactions between seaweeds and fouling organisms. We also conclude, that with careful choice of solvent and extraction time, the surface extraction procedure described here may be broadly useful for investigating the deterrent effects of seaweed surface metabolites against fouling organisms

The oviduct in chaos

The unilateral avian oviduct is divisible into five functional regions which, moving distally, include the infundibulum, magnum, isthmus, tubular shell gland and shell gland pouch. Each region subserves a variety of functions, which through their interaction give rise to the multilayered albumen, shell membranes and the organichnorganic complex, which comprises the shell. The sequential activity of these structurally diverse regions is a necessary prerequisite for "normal" egg formation. The reproductive effort can be influenced by a number of disease processes either directly by virtue of the fact that they alter the ability of the lining cells to synthesise their integral components or indirect by generally compromising bird health. Notable amongst the former are Infectious Bronchitis, Newcastle Disease and Egg Drop Syndrome. All change the quality of the final product in terms of the shape and texture of the shell. In recent years it has become evident that environmental stress has an equally, if not more, important role to play in oviduct disfunction. In the absence of large areas of functional surface epithelium, the eggs laid were structurally defective at all levels from the mammillary layer outwards. As the epithelial layers regenerated, shell quality approximated normality, but never returned to the pre-stress condition. The process of candling signals amongst other internal defects a variety of inclusions variously classified as blood and meat spots. They are quite specific in their locations; thus blood spots originating from the rupture of ovarian blood vessels at ovulation, are invariably confined to the periphery of the yolk mass, while meat spots now classified according to their composition are confined to albumen. Within the latter they are recognised as tissue rich deposits, the result of oviduct breakdown and/or calcium rich fragments. The latter implies a breach in the barrier provided by the soft shell membranes

Sterilisation of incompetent mentally handicapped persons: a model for decision making.

Doctors are regularly confronted with requests for sterilisation of mentally handicapped people who cannot give consent for themselves. They ought to act in a medical vacuum because there doesn't exist a consensus about a model for decision making on this matter. In this article a model for decision making is proposed, based on a review of the literature and our own research data. We have attempted to select and classify certain factors which could enable us to arrive at an ethically justifiable method of making a medical decision. In doing so we distinguish two major criteria: heredity and parenting competence, and six minor criteria: conception risk, IQ, age, personality, medical aspects and prognosis and finally support and guidance for the mentally handicapped person. The major criteria give rise to a "situation of necessity". In this situation the physician is confronted with a conflict of values and interests. The minor criteria are of an entirely different ethical order. They can only be considered once the major criteria have created a "situation of necessity". Ultimately it comes down to deciding whether the benefits of sterilisation outweigh the drawbacks and whether the means are appropriate to the end, where efficient contraception is the end and irreversible sterilisation is the means