Taxonomy classification depth comparisons among V region datasets and the FL variants.

<p>Taxonomy classification depth comparisons among V region datasets and the FL variants.</p

Classification of the full-length sequences and their trimmed to the examined V region variants.

<p>Classification of the full-length sequences and their trimmed to the examined V region variants.</p

Taxonomy, OTU (3% sequence distance) analysis and Unifrac results of the performed simulation.

<p>A) PCA results of matrix generated by sample distances based on classified sequence relative abundance (left) and presence absence (right) for the V regions and FL datasets. B) Similarly to A for OTU relative abundance (left) and presence absence (right). C) PCA results for matrices generated using the weighted (left - phylotype relative abundance based) and unweighted (right - phylotype occurrence based) Unifrac analysis result distances between samples for the V regions and FL datasets.</p

Pearson correlation tests between corresponding sequence distances of examined V regions and FL variants.

<p>All tests were significant (P<001). Test correlation index (r) values and linear models (presented with solid lines) used to describe overall trends are provided above and below each plot. Local relationships between corresponding sequence distances of the FL and other datasets are expressed with the non-parametric LOWESS (locally weighted regression and smoothing scatterplots) regression analysis plotting (dot-dashed lines), while the ideal y = x correlation is also plotted (dashed lines).</p

16S rRNA gene sequence conservation of soil derived sequences.

<p>A) Nucleic acid base composition of the 16S rRNA gene consensus sequence of the 41,109 RDP database soil derived sequences for 90% conservation cutoff value. Red background positions include hypervariable stretches as reported in reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042671#pone.0042671-Baker1" target="_blank">[24]</a> and expanded in the current study, while green background positions are proposed primer designing sites in reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042671#pone.0042671-Wang1" target="_blank">[11]</a>. The IUPAC system was used for denoting per base variability (degeneracies) and lower-case letters are used for nucleotide positions where gaps participated by more than 10% in the position throughout the sequence alignment. B) Comparison of present study results for 95% sequence conservation with the ones provided in reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042671#pone.0042671-Wang1" target="_blank">[11]</a> for 90% sequence conservation. Letter color coding referring to differences found on sequences of this study compared to that of reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042671#pone.0042671-Wang1" target="_blank">[11]</a>: red) increased variability; blue) altered degeneracy without variability increase; green) reduced variability; grey) although presence of two nucleotides in that position is implied in reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042671#pone.0042671-Wang1" target="_blank">[11]</a>, these are missing in the published table.</p

Study methods overview.

<p>Study methods overview.</p

Distribution of commonly screened V region fragment lengths.

<p>Fragment lengths including the examined hypervariable regions for all screened (41,109) sequences. Sequence fragments were plotted according to length ascending order.</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