Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and thus reduces serum IgG concentrations, including autoantibodies. The objective of this study was to evaluate the efficacy and safety of efgartigimod in adults with persistent and chronic primary immune thrombocytopenia. METHODS: This phase 3, multicentre, randomised, double-blinded, placebo-controlled, 24-week study evaluated the efficacy and safety of intravenous efgartigimod in adults aged 18 years or older with chronic or persistent primary immune thrombocytopenia who had an average platelet count of less than 30 000, had responded to at least one previous immune thrombocytopenia therapy, and were on a concurrent therapy at baseline or had received at least a second previous immune thrombocytopenia therapy. The study took place in 71 participating sites from Asia, Europe, and North America. Patients were randomly assigned 2:1 to receive either efgartigimod (10 mg/kg) or placebo intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients' platelet count. The primary endpoint, evaluated in the chronic population, was sustained platelet count response (≥50 × 109 for at least 4 of the last 6 weeks). This study is registered with ClinicalTrials.gov (NCT04188379) and is completed. FINDINGS: A total of 205 patients were screened from Dec 9, 2019, to Feb 3, 2022, and 131 (86 in the efgartigimod group; 45 in the placebo group) were randomly assigned. These patients represented a population with long-term disease who had a mean time since diagnosis of 10·6 years and 67% (88/131) of whom had received at least three previous immune thrombocytopenia treatments. 22% (17/78) of patients with chronic immune thrombocytopenia receiving efgartigimod reached the primary endpoint compared with 5% (2/40) of those receiving placebo (p=0·032; adjusted difference in response, 16% [95% CI 2·6-26·4]). The median number of weeks of disease control in patients with chronic immune thrombocytopenia was 2·0 (IQR 0·0-11·0) for efgartigimod versus 0·0 (0·0-1·0) for placebo (p=0·0009). Efgartigimod was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in efgartigimod and 13% in placebo), haematuria (16% in efgartigimod and 16% in placebo), and petechiae (15% in efgartigimod and 27% in placebo). INTERPRETATION: Efgartigimod significantly increased sustained platelet count responses compared with placebo in patients with chronic immune thrombocytopenia, including those who had received multiple previous immune thrombocytopenia therapies. Upon completion of the ADVANCE IV study, patients could enroll in the ongoing open-label extension. Subcutaneous efgartigimod is currently being evaluated in patients with immune thrombocytopenia in the ADVANCE SC+ trial. FUNDING: argenx.

Seasonality modifies the effect of a lipid-based nutrient supplement for pregnant rural women on birth length.

BACKGROUND: Maternal nutritional status is a major determinant of low birth weight and fluctuates across seasons. Seasonality may influence the outcome of prenatal nutrition interventions that aim to enhance fetal growth. OBJECTIVE: This study investigated seasonal modifications of the efficacy of a randomized controlled prenatal nutrition intervention trial in pregnant women to improve fetal growth in rural Burkina Faso. METHODS: The second Micronutriments et Santé de la Mère et de l'Enfant study compared a lipid-based nutrient supplement (LNS) fortified with multiple micronutrients (MMNs) to an MMN supplement. Truncated Fourier series were used to characterize seasonality in birth outcomes. Models that included the Fourier series and newborn and maternal characteristics were used to assess seasonal effect modifications of prenatal supplementation on birth outcomes. RESULTS: Birth weight, birth length, small for gestational age as a proxy for intrauterine growth retardation, and preterm birth were significantly related to date of birth and showed important seasonal variations. LNSs, which supply energy in addition to MMNs, resulted in a significant increase in birth length (+13.5 mm, 95% CI: 6.5, 20.5 mm) at the transition from rain to dry season (September to November) compared to MMNs alone. CONCLUSIONS: The climatologic and agricultural seasonal patterns in Burkina Faso affect the efficacy of prenatal LNSs on birth length. In this context, prenatal MMN supplementation programs should be complemented by energy supplementation during the annual rain season to promote fetal growth. This trial was registered at clinicaltrials.gov as NCT00909974.

Leaf responses to mild drought stress in natural variants of Arabidopsis.

Although the response of plants exposed to severe drought stress has been studied extensively, little is known about how plants adapt their growth under mild drought stress conditions. Here, we analyzed the leaf and rosette growth response of six Arabidopsis (Arabidopsis thaliana) accessions originating from different geographic regions when exposed to mild drought stress. The automated phenotyping platform WIWAM was used to impose stress early during leaf development, when the third leaf emerges from the shoot apical meristem. Analysis of growth-related phenotypes showed differences in leaf development between the accessions. In all six accessions, mild drought stress reduced both leaf pavement cell area and number without affecting the stomatal index. Genome-wide transcriptome analysis (using RNA sequencing) of early developing leaf tissue identified 354 genes differentially expressed under mild drought stress in the six accessions. Our results indicate the existence of a robust response over different genetic backgrounds to mild drought stress in developing leaves. The processes involved in the overall mild drought stress response comprised abscisic acid signaling, proline metabolism, and cell wall adjustments. In addition to these known severe drought-related responses, 87 genes were found to be specific for the response of young developing leaves to mild drought stress.

Analysis of tiling array expression studies with flexible designs in Bioconductor (waveTiling).

BACKGROUND: Existing statistical methods for tiling array transcriptome data either focus on transcript discovery in one biological or experimental condition or on the detection of differential expression between two conditions. Increasingly often, however, biologists are interested in time-course studies, studies with more than two conditions or even multiple-factor studies. As these studies are currently analyzed with the traditional microarray analysis techniques, they do not exploit the genome-wide nature of tiling array data to its full potential. RESULTS: We present an R Bioconductor package, waveTiling, which implements a wavelet-based model for analyzing transcriptome data and extends it towards more complex experimental designs. With waveTiling the user is able to discover (1) group-wise expressed regions, (2) differentially expressed regions between any two groups in single-factor studies and in (3) multifactorial designs. Moreover, for time-course experiments it is also possible to detect (4) linear time effects and (5) a circadian rhythm of transcripts. By considering the expression values of the individual tiling probes as a function of genomic position, effect regions can be detected regardless of existing annotation. Three case studies with different experimental set-ups illustrate the use and the flexibility of the model-based transcriptome analysis. CONCLUSIONS: The waveTiling package provides the user with a convenient tool for the analysis of tiling array trancriptome data for a multitude of experimental set-ups. Regardless of the study design, the probe-wise analysis allows for the detection of transcriptional effects in both exonic, intronic and intergenic regions, without prior consultation of existing annotation.

Transparent exopolymer particle removal in different drinking water production centers.

Transparent exopolymer particles (TEP) have recently gained interest in relation to membrane fouling. These sticky, gel-like particles consist of acidic polysaccharides excreted by bacteria and algae. The concentrations, expressed as xanthan gum equivalents L⁻¹ (µg X(eq) L⁻¹), usually reach hundred up to thousands µg X(eq) L⁻¹ in natural waters. However, very few research was performed on the occurrence and fate of TEP in drinking water, this far. This study examined three different drinking water production centers, taking in effluent of a sewage treatment plant (STP), surface water and groundwater, respectively. Each treatment step was evaluated on TEP removal and on 13 other chemical and biological parameters. An assessment on TEP removal efficiency of a diverse range of water treatment methods and on correlations between TEP and other parameters was performed. Significant correlations between particulate TEP (>0.4 µm) and viable cell concentrations were found, as well as between colloidal TEP (0.05-0.4 µm) and total COD, TOC, total cell or viable cell concentrations. TEP concentrations were very dependent on the raw water source; no TEP was detected in groundwater but the STP effluent contained 1572 µg X(eq) L⁻¹ and the surface water 699 µg X(eq) L⁻¹. Over 94% of total TEP in both plants was colloidal TEP, a fraction neglected in nearly every other TEP study. The combination of coagulation and sand filtration was effective to decrease the TEP levels by 67%, while the combination of ultrafiltration and reverse osmosis provided a total TEP removal. Finally, in none of the installations TEP reached the final drinking water distribution system at significant concentrations. Overall, this study described the presence and removal of TEP in drinking water systems.

Fast wavelet based functional models for transcriptome analysis with tiling arrays.

For a better understanding of the biology of an organism, a complete description is needed of all regions of the genome that are actively transcribed. Tiling arrays are used for this purpose. They allow for the discovery of novel transcripts and the assessment of differential expression between two or more experimental conditions such as genotype, treatment, tissue, etc. In tiling array literature, many efforts are devoted to transcript discovery, whereas more recent developments also focus on differential expression. To our knowledge, however, no methods for tiling arrays have been described that can simultaneously assess transcript discovery and identify differentially expressed transcripts. In this paper, we adopt wavelet based functional models to the context of tiling arrays. The high dimensionality of the data triggered us to avoid inference based on Bayesian MCMC methods. Instead, we introduce a fast empirical Bayes method that provides adaptive regularization of the functional effects. A simulation study and a case study illustrate that our approach is well suited for the simultaneous assessment of transcript discovery and differential expression in tiling array studies, and that it outperforms methods that accomplish only one of these tasks.