Representative histological sections from healthy (a, b and c) and blister-affected (d, e and f) <i>Echinopora lamellosa</i> tissues embedded in LR white resin.

<p>Blister sections were taken at the blister-affected interface. A) and d) Survey sections stained with toluidine blue (E = epidermis, G = gastrodermis and Me = mesoglea). B) and e) Sections stained with acridine orange for the detection of bacteria, as visualised by red fluorescence. In this case, red fluorescence is attributed to autofluorescence of symbiotic algae nuclei and coral mucus (Mu). C) and f) Nigrosin staining, targeting necrotic tissues. Scale bars = 10 µm.</p

Histological sections of growth anomalies (GA) only identified in blister-affected samples embedded in LR white resin.

<p>A) and d) Survey sections stained with toluidine blue. B) and e) Sections stained with acridine orange for the detection of bacteria, as visualised by red fluorescence. In this case, red fluorescence is attributed to autofluorescence of host nuclei (e.g. mucocyte nuclei). C) and f) Nigrosin staining, targeting necrotic tissues. Block arrow indicates epithelium separated from underlying tissue, revealing a cleft (represented by the asterisk). Dashed arrow highlights growth from a centralised area. Scale bars = 10 µm.</p

Patient Involvement in Preparing Clinical Research Peer-Reviewed Publications or Results Summaries: A Systematic Review

<div><b>Objective</b></div><div>Although patient involvement in results reporting is being encouraged, relevant evidence must be assessed before developing best practice guidelines. Our objective was to conduct the first systematic literature review on the effects of patient involvement on results reporting.</div><div><br></div><div><b>Research design and methods</b></div><div>Patient experts and publication professionals co-created a PRISMA-P protocol (PROSPERO registration submitted). Using MeSH terms and OVID, we searched (10/09/2017) MEDLINE, EMBASE and Cochrane databases (all languages; 01/01/2015–10/09/2017) and secondary sources. Eligible articles had to report on the effects of having patients author or contribute to clinical research peer reviewed publications or summaries. The primary outcome was the number of articles investigating patient authorship or contribution to peer-reviewed publications. For included articles, we assessed bias risk (Newcastle-Ottawa Scale).</div><div><br></div><div><b>Results</b></div><div>Of the 105 database articles retrieved, 24 duplicates were removed. Title/abstract screening excluded 62 articles. From full-text screening of 19 articles, we could include 2. Both focused on the effects of patient involvement for preparing peer-reviewed publications. Evidence quality for each article was poor/fair (0 randomised controlled trials). Reported benefits of patient involvement included meeting funder requirements, critical and unique contributions, new research ideas, improved reporting, patient empowerment and new skill development (patients and researchers). Reported harms included the need for additional time, training, resources and budget. </div><div><br></div><div><b>Conclusions</b></div><div>This systematic review identified a major evidence gap that must be addressed to guide best practices for patient involvement in results reporting. Patients, sponsors and publication professionals could co-create a research priority list and use emerging evidence to draft interim guidelines for ethical and meaningful involvement of patients in results reporting.</div

DataSheet_1_Microfluidic antibody profiling after repeated SARS-CoV-2 vaccination links antibody affinity and concentration to impaired immunity and variant escape in patients on anti-CD20 therapy.pdf

BackgroundPatients with autoimmune/inflammatory conditions on anti-CD20 therapies, such as rituximab, have suboptimal humoral responses to vaccination and are vulnerable to poorer clinical outcomes following SARS-CoV-2 infection. We aimed to examine how the fundamental parameters of antibody responses, namely, affinity and concentration, shape the quality of humoral immunity after vaccination in these patients.MethodsWe performed in-depth antibody characterisation in sera collected 4 to 6 weeks after each of three vaccine doses to wild-type (WT) SARS-CoV-2 in rituximab-treated primary vasculitis patients (n = 14) using Luminex and pseudovirus neutralisation assays, whereas we used a novel microfluidic-based immunoassay to quantify polyclonal antibody affinity and concentration against both WT and Omicron (B.1.1.529) variants. We performed comparative antibody profiling at equivalent timepoints in healthy individuals after three antigenic exposures to WT SARS-CoV-2 (one infection and two vaccinations; n = 15) and in convalescent patients after WT SARS-CoV-2 infection (n = 30).ResultsRituximab-treated patients had lower antibody levels and neutralisation titres against both WT and Omicron SARS-CoV-2 variants compared to healthy individuals. Neutralisation capacity was weaker against Omicron versus WT both in rituximab-treated patients and in healthy individuals. In the rituximab cohort, this was driven by lower antibody affinity against Omicron versus WT [median (range) KD: 21.6 (9.7–38.8) nM vs. 4.6 (2.3–44.8) nM, p = 0.0004]. By contrast, healthy individuals with hybrid immunity produced a broader antibody response, a subset of which recognised Omicron with higher affinity than antibodies in rituximab-treated patients [median (range) KD: 1.05 (0.45–1.84) nM vs. 20.25 (13.2–38.8) nM, p = 0.0002], underpinning the stronger serum neutralisation capacity against Omicron in the former group. Rituximab-treated patients had similar anti-WT antibody levels and neutralisation titres to unvaccinated convalescent individuals, despite two more exposures to SARS-CoV-2 antigen. Temporal profiling of the antibody response showed evidence of affinity maturation in healthy convalescent patients after a single SARS-CoV-2 infection, which was not observed in rituximab-treated patients, despite repeated vaccination.DiscussionOur results enrich previous observations of impaired humoral immune responses to SARS-CoV-2 in rituximab-treated patients and highlight the significance of quantitative assessment of serum antibody affinity and concentration in monitoring anti-viral immunity, viral escape, and the evolution of the humoral response.</p

Expert prior opinion before introduction of the MYCYC data regarding 6-month remission rates using treatment with CYC or MMF for children with PAN.

<p><b>Reprinted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120981#pone.0120981.ref007" target="_blank">7</a>] under a CC BY license, with permission from the authors, original copyright 2014.</b> Prior opinion was that the most likely value for p_C was 0.7; 90% and 50% credibility intervals were (0.30, 0.91) and (0.50, 0.78), respectively. The effective sample size was 5 patients on CYC. The prior for p_M is derived from those for p_C and θ. It had mode = 0.65; 90% and 50% credibility intervals were (0.21, 0.90) and (0.41, 0.74), respectively.</p

Flow diagram illustrating the sequence of activities undertaken during the MYPAN prior elicitation meeting and the time allocated to each activity.

<p>Flow diagram illustrating the sequence of activities undertaken during the MYPAN prior elicitation meeting and the time allocated to each activity.</p

Comparison of the design of 2 randomised controlled trials for vasculitis: MYPAN versus MYCYC.

<p>^aMYPAN: Mycophenolate mofetil for childhood polyarteritis nodosa;</p><p>^bPAN: polyarteritis nodosa;</p><p>^cMYCYC: Mycophenolate mofetil versus cyclophosphamide for ANCA associated vasculitis;</p><p>^dANCA: anti neutrophil cytoplasmic antibodies;</p><p>^eMMF: Mycophenolate mofetil;</p><p>^fCYC: cyclophosphamide;</p><p>^gPVAS: Paediatric Vasculitis Activity Score;</p><p>^hBVAS: Birmingham Vasculitis Activity Score.</p><p>Comparison of the design of 2 randomised controlled trials for vasculitis: MYPAN versus MYCYC.</p

Influence of the MYCYC trial results on expert prior opinion regarding 6-month remission rates using treatment with CYC or MMF for children with PAN. Reprinted from [7] under a CC BY license, with permission from the authors, original copyright 2014.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120981#pone.0120981.g004" target="_blank">Fig 4A</a>): Influence of MYCYC results on prior opinion for p_C. The modified prior distribution for p_C after considering the MYCYC results had mode = 0.74; 90% and 50% credibility intervals were (0.51, 0.86) and (0.63, 0.78), respectively. This level of certainty is equivalent to what would be obtained from a clinical trial involving 17 patients treated with CYC (effective sample size). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120981#pone.0120981.g004" target="_blank">Fig 4B</a>): Influence of MYCYC results on prior opinion for p_M. The modified prior for p_M after considering the MYCYC results had mode = 0.71; 90% and 50% credibility intervals were (0.45, 0.85) and (0.59, 0.76), respectively. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120981#pone.0120981.g004" target="_blank">Fig 4C</a>): Comparison of the final expert prior opinions for p_C and p_M incorporating the MYCYC data.</p

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window).Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p Background Methods Findings Interpretation Funding</p

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p