Evolution of the Grain Dispersal System in Barley.

About 12,000 years ago in the Near East, humans began the transition from hunter-gathering to agriculture-based societies. Barley was a founder crop in this process, and the most important steps in its domestication were mutations in two adjacent, dominant, and complementary genes, through which grains were retained on the inflorescence at maturity, enabling effective harvesting. Independent recessive mutations in each of these genes caused cell wall thickening in a highly specific grain "disarticulation zone," converting the brittle floral axis (the rachis) of the wild-type into a tough, non-brittle form that promoted grain retention. By tracing the evolutionary history of allelic variation in both genes, we conclude that spatially and temporally independent selections of germplasm with a non-brittle rachis were made during the domestication of barley by farmers in the southern and northern regions of the Levant, actions that made a major contribution to the emergence of early agrarian societies.

SWEET11b transports both sugar and cytokinin in developing barley grains.

Even though Sugars Will Eventually be Exported Transporters (SWEETs) have been found in every sequenced plant genome, a comprehensive understanding of their functionality is lacking. In this study, we focused on the SWEET family of barley (Hordeum vulgare). A radiotracer assay revealed that expressing HvSWEET11b in African clawed frog (Xenopus laevis) oocytes facilitated the bidirectional transfer of not only just sucrose and glucose, but also cytokinin. Barley plants harboring a loss-of-function mutation of HvSWEET11b could not set viable grains, while the distribution of sucrose and cytokinin was altered in developing grains of plants in which the gene was knocked down. Sucrose allocation within transgenic grains was disrupted, which is consistent with the changes to the cytokinin gradient across grains, as visualized by magnetic resonance imaging and Fourier transform infrared spectroscopy microimaging. Decreasing HvSWEET11b expression in developing grains reduced overall grain size, sink strength, the number of endopolyploid endosperm cells, and the contents of starch and protein. The control exerted by HvSWEET11b over sugars and cytokinins likely predetermines their synergy, resulting in adjustments to the grain's biochemistry and transcriptome.

Using latent class analysis to investigate enduring effects of intersectional social disadvantage on long-term vocational and financial outcomes in the 20-year prospective Chicago Longitudinal Study.

BACKGROUND: Class and social disadvantage have long been identified as significant factors in the etiology and epidemiology of psychosis. Few studies have explicitly examined the impact of intersecting social disadvantage on long-term employment and financial independence. METHODS: We applied latent class analysis (LCA) to 20-year longitudinal data from participants with affective and non-affective psychosis (n = 256) within the Chicago Longitudinal Research. LCA groups were modeled using multiple indicators of pre-morbid disadvantage (parental social class, educational attainment, race, gender, and work and social functioning prior to psychosis onset). The comparative longitudinal work and financial functioning of LCA groups were then examined. RESULTS: We identified three distinct latent classes: one comprised entirely of White participants, with the highest parental class and highest levels of educational attainment; a second predominantly working-class group, with equal numbers of Black and White participants; and a third with the lowest parental social class, lowest levels of education and a mix of Black and White participants. The latter, our highest social disadvantage group experienced significantly poorer employment and financial outcomes at all time-points, controlling for diagnosis, symptoms, and hospitalizations prior to baseline. Contrary to our hypotheses, on most measures, the two less disadvantaged groups did not significantly differ from each other. CONCLUSIONS: Our analyses add to a growing literature on the impact of multiple forms of social disadvantage on long-term functional trajectories, underscoring the importance of proactive attention to sociostructural disadvantage early in treatment, and the development and evaluation of interventions designed to mitigate ongoing social stratification.

Investigating the genetic control of plant development in spring barley under speed breeding conditions.

KEY MESSAGE: This study found that the genes, PPD-H1 and ELF3, control the acceleration of plant development under speed breeding, with important implications for optimizing the delivery of climate-resilient crops. Speed breeding is a tool to accelerate breeding and research programmes. Despite its success and growing popularity with breeders, the genetic basis of plant development under speed breeding remains unknown. This study explored the developmental advancements of barley genotypes under different photoperiod regimes. A subset of the HEB-25 Nested Association Mapping population was evaluated for days to heading and maturity under two contrasting photoperiod conditions: (1) Speed breeding (SB) consisting of 22 h of light and 2 h of darkness, and (2) normal breeding (NB) consisting of 16 h of light and 8 h of darkness. GWAS revealed that developmental responses under both conditions were largely controlled by two loci: PPDH-1 and ELF3. Allelic variants at these genes determine whether plants display early flowering and maturity under both conditions. At key QTL regions, domesticated alleles were associated with late flowering and maturity in NB and early flowering and maturity in SB, whereas wild alleles were associated with early flowering under both conditions. We hypothesize that this is related to the dark-dependent repression of PPD-H1 by ELF3 which might be more prominent in NB conditions. Furthermore, by comparing development under two photoperiod regimes, we derived an estimate of plasticity for the two traits. Interestingly, plasticity in development was largely attributed to allelic variation at ELF3. Our results have important implications for our understanding and optimization of speed breeding protocols particularly for introgression breeding and the design of breeding programmes to support the delivery of climate-resilient crops.

GWAS scans of cereal cyst nematode (Heterodera avenae) resistance in Indian wheat germplasm.

Significant yield losses in major cereal-growing regions around the world have been linked to cereal cyst nematodes (Heterodera spp.). Identifying and deploying natural sources of resistance is of utmost importance due to increasing concerns associated with chemical methods over the years. We screened 141 diverse wheat genotypes collected from pan-Indian wheat cultivation states for nematode resistance over two years, alongside two resistant (Raj MR1, W7984 (M6)) and two susceptible (WH147, Opata M85) checks. We performed genome-wide association analysis using four single-locus models (GLM, MLM, CMLM, and ECMLM) and three multi-locus models (Blink, FarmCPU, and MLMM). Single locus models identified nine significant MTAs (-log10 (P) > 3.0) on chromosomes 2A, 3B, and 4B whereas, multi-locus models identified 11 significant MTAs on chromosomes 1B, 2A, 3B, 3D and 4B. Single and multi-locus models identified nine common significant MTAs. Candidate gene analysis identified 33 genes like F-box-like domain superfamily, Cytochrome P450 superfamily, Leucine-rich repeat, cysteine-containing subtype Zinc finger RING/FYVE/PHD-type, etc., having a putative role in disease resistance. Such genetic resources can help to reduce the impact of this disease on wheat production. Additionally, these results can be used to design new strategies for controlling the spread of H. avenae, such as the development of resistant varieties or the use of resistant cultivars. Finally, the obtained results can also be used to identify new sources of resistance to this pathogen and develop novel control methods.

Wheat genetic loci conferring resistance to stripe rust in the face of genetically diverse races of the fungus Puccinia striiformis f. sp. tritici.

KEY MESSAGE: Analysis of a wheat multi-founder population identified 14 yellow rust resistance QTL. For three of the four most significant QTL, haplotype analysis indicated resistance alleles were rare in European wheat. Stripe rust, or yellow rust (YR), is a major fungal disease of wheat (Triticum aestivum) caused by Puccinia striiformis Westend f. sp. tritici (Pst). Since 2011, the historically clonal European Pst races have been superseded by the rapid incursion of genetically diverse lineages, reducing the resistance of varieties previously showing durable resistance. Identification of sources of genetic resistance to such races is a high priority for wheat breeding. Here we use a wheat eight-founder multi-parent population genotyped with a 90,000 feature single nucleotide polymorphism array to genetically map YR resistance to such new Pst races. Genetic analysis of five field trials at three UK sites identified 14 quantitative trait loci (QTL) conferring resistance. Of these, four highly significant loci were consistently identified across all test environments, located on chromosomes 1A (QYr.niab-1A.1), 2A (QYr.niab-2A.1), 2B (QYr.niab-2B.1) and 2D (QYr.niab-2D.1), together explaining ~ 50% of the phenotypic variation. Analysis of these four QTL in two-way and three-way combinations showed combinations conferred greater resistance than single QTL, and genetic markers were developed that distinguished resistant and susceptible alleles. Haplotype analysis in a collection of wheat varieties found that the haplotypes associated with YR resistance at three of these four major loci were rare (≤ 7%) in European wheat, highlighting their potential utility for future targeted improvement of disease resistance. Notably, the physical interval for QTL QYr.niab-2B.1 contained five nucleotide-binding leucine-rich repeat candidate genes with integrated BED domains, of which two corresponded to the cloned resistance genes Yr7 and Yr5/YrSp.

Trends of genetic changes uncovered by Env- and Eigen-GWAS in wheat and barley.

KEY MESSAGE: Variety age and population structure detect novel QTL for yield and adaptation in wheat and barley without the need to phenotype. The process of crop breeding over the last century has delivered new varieties with increased genetic gains, resulting in higher crop performance and yield. However, in many cases, the alleles and genomic regions underpinning this success remain unknown. This is partly due to the difficulty of generating sufficient phenotypic data on large numbers of historical varieties to enable such analyses. Here we demonstrate the ability to circumvent such bottlenecks by identifying genomic regions selected over 100 years of crop breeding using age of a variety as a surrogate for yield. Rather than collecting phenotype data, we deployed 'environmental genome-wide association scans' (EnvGWAS) based on variety age in two of the world's most important crops, wheat and barley, and detected strong signals of selection across both genomes. EnvGWAS identified 16 genomic regions in barley and 10 in wheat with contrasting patterns between spring and winter types of the two crops. To further examine changes in genome structure, we used the genomic relationship matrix of the genotypic data to derive eigenvectors for analysis in EigenGWAS. This detected seven major chromosomal introgressions that contributed to adaptation in wheat. EigenGWAS and EnvGWAS based on variety age avoid costly phenotyping and facilitate the identification of genomic tracts that have been under selection during breeding. Our results demonstrate the potential of using historical cultivar collections coupled with genomic data to identify chromosomal regions under selection and may help guide future plant breeding strategies to maximise the rate of genetic gain and adaptation.

Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor.

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

Multi-locus genome-wide association mapping for spike-related traits in bread wheat (Triticum aestivum L.).

BACKGROUND: Bread wheat (Triticum aestivum L.) is one of the most important cereal food crops for the global population. Spike-layer uniformity (the consistency of the spike distribution in the vertical space)-related traits (SLURTs) are quantitative and have been shown to directly affect yield potential by modifying the plant architecture. Therefore, these parameters are important breeding targets for wheat improvement. The present study is the first genome-wide association study (GWAS) targeting SLURTs in wheat. In this study, a set of 225 diverse spring wheat accessions were used for multi-locus GWAS to evaluate SLURTs, including the number of spikes per plant (NSPP), spike length (SL), number of spikelets per spike (NSPS), grain weight per spike (GWPS), lowest tiller height (LTH), spike-layer thickness (SLT), spike-layer number (SLN) and spike-layer uniformity (SLU). RESULTS: In total, 136 significant marker trait associations (MTAs) were identified when the analysis was both performed individually and combined for two environments. Twenty-nine MTAs were detected in environment one, 48 MTAs were discovered in environment two and 59 MTAs were detected using combined data from the two environments. Altogether, 15 significant MTAs were found for five traits in one of the two environments, and four significant MTAs were detected for the two traits, LTH and SLU, in both environments i.e. E1, E2 and also in combined data from the two environments. In total, 279 candidate genes (CGs) were identified, including Chaperone DnaJ, ABC transporter-like, AP2/ERF, SWEET sugar transporter, as well as genes that have previously been associated with wheat spike development, seed development and grain yield. CONCLUSIONS: The MTAs detected through multi-locus GWAS will be useful for improving SLURTs and thus yield in wheat production through marker-assisted and genomic selection.

Northwell intracoronary brachytherapy for the treatment of recurrent drug eluting stent in-stent restenosis (NITDI study group).

OBJECTIVE: The purpose of this study is to report on safety, short-term and long-term clinical efficacy following intracoronary brachytherapy (ICBT) for restenosis (ISR) in patients with drug eluting stents (DES). BACKGROUND: ICBT is an effective treatment for ISR of bare metal stents (BMS) but its utilization has waned due to the advent of DES. ISR following DES occurs at a frequency of 8% or greater. METHOD: A retrospective analysis was performed on patients treated on an institutional review board (IRB) approved protocol using ICBT for DES ISR between January 2011 and October 2016. All patients were followed for 24 months for procedural complications, mortality, clinical ISR/target lesion revascularization (TLR) and stroke. RESULTS: A total of 290 patients were identified with a mean age of 66.6 years. All of them had high rates of typical coronary artery disease risk factors. Our primary outcome, composite of in-hospital mortality, myocardial infarction (MI), safety outcomes and procedural failure was noted in 1(0.3%) patient who had a MI. No other secondary outcome was noted in-hospital. At 1-year follow up, 12.4% patients had ISR, 1.7% patients died, and 1 (0.3%) had ischemic stroke. At 2-year, 14.7% had ISR, and total 6 (2.1%) patients had MI. CONCLUSION: ICBT demonstrates excellent technical success rates for treatment, safety, and reasonable efficacy over 2-years to be free from recurrent clinical ISR. This study represents the largest ICBT data for DES ISR to date among very complex lesion subsets, however, more prospective data will be needed to determine the optimal patient for treatment.

Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19).

Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B0AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.

Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors.

Herein we describe the design, synthesis and anticancer evaluation of a series of 2,3-dihydroimidazo[2,1-b]thiazoles as dual kinase inhibitors of IGF1R and EGFR. A series of saturated dihydroimidazo[2,1-b] thiazoles were synthesized to understand the structure-activity relationship. Further, the key modifications were performed to improve drug like properties of the series. A 2-oxa-6-azaspiro [3.3] heptane moiety was incorporated as a bioisosteric replacement of morpholine on dihydroimidazo[2,1-b] thiazole scaffold.Subsequent structure-activity relationship (SAR) studies identified several compounds with nM range of activity. The compound 18a shows promising activity, IC50 = 52 nM against IGF1R and IC50 = 35.5 nM against EGFR with descent PK profile. The identified leadshows promising activity against both wild type and the T790M mutant forms of enzymes.

Acute kidney injury, stroke and death after cardiopulmonary bypass surgery: the role of perfusion flow and pressure.

INTRODUCTION: Acute kidney injury after cardiopulmonary bypass surgery is associated with morbidity and mortality. This study aims to evaluate the role of low perfusion flow and pressure in the development of cardiopulmonary bypass-associated acute kidney injury, stroke and death, using multicentre registry data. METHODS: We identified patients from the Australian and New Zealand Collaborative Perfusion Registry who underwent coronary artery bypass grafting and/or valvular surgery between 2008 and 2018. Primary predictor variables were the length of time the perfusion flow was <1.6 L/min/m2 and the length of time perfusion pressure was < 50mmHg. The primary outcome was new postoperative acute kidney injury defined by the risk-injury-failure-loss-end stage criteria. Secondary outcomes were stroke and in-hospital death. The influence of perfusion flow and pressure during cardiopulmonary bypass on the primary and secondary outcomes was estimated using separate multivariate models. RESULTS: A total of 16,356 patients were included. The mean age was 66 years and 75% were male. Acute kidney injury was observed in 1,844 patients (11%), stroke in 204 (1.3%) and in-hospital death in 286 (1.8%). Neither the duration of the time spent for perfusion flow (<1.6 L/minute/m2) nor the duration of the time spent for perfusion pressure (<50 mmHg) was associated with postoperative acute kidney injury, stroke or death in adjusted models. CONCLUSIONS: Neither low perfusion pressure nor low perfusion flow during cardiopulmonary bypass were predictive of postoperative acute kidney injury, stroke or death.

Mediators of Discrimination in Primary Care Appointment Access.

We examine how differences in questions asked and information provided by physicians' offices contribute to differences in new-patient appointment offers. Data is from a 2013-16 field experiment involving calls to a random sample of US primary care physicians on behalf of simulated new patients differentiated by race/ethnicity (Black, Hispanic, White), sex, and insurance. We find that the rates and stated reasons for denial of appointment offers differ substantially across patient groups.

The highly divergent Jekyll genes, required for sexual reproduction, are lineage specific for the related grass tribes Triticeae and Bromeae.

Phylogenetically related groups of species contain lineage-specific genes that exhibit no sequence similarity to any genes outside the lineage. We describe here that the Jekyll gene, required for sexual reproduction, exists in two much diverged allelic variants, Jek1 and Jek3. Despite low similarity, the Jek1 and Jek3 proteins share identical signal peptides, conserved cysteine positions and direct repeats. The Jek1/Jek3 sequences are located at the same chromosomal locus and inherited in a monogenic Mendelian fashion. Jek3 has a similar expression as Jek1 and complements the Jek1 function in Jek1-deficient plants. Jek1 and Jek3 allelic variants were almost equally distributed in a collection of 485 wild and domesticated barley accessions. All domesticated barleys harboring the Jek1 allele belong to single haplotype J1-H1 indicating a genetic bottleneck during domestication. Domesticated barleys harboring the Jek3 allele consisted of three haplotypes. Jekyll-like sequences were found only in species of the closely related tribes Bromeae and Triticeae but not in other Poaceae. Non-invasive magnetic resonance imaging revealed intrinsic grain structure in Triticeae and Bromeae, associated with the Jekyll function. The emergence of Jekyll suggests its role in the separation of the Bromeae and Triticeae lineages within the Poaceae and identifies the Jekyll genes as lineage-specific.

Natural variation in meiotic recombination rate shapes introgression patterns in intraspecific hybrids between wild and domesticated barley.

Meiotic recombination rates vary considerably between species, populations and individuals. The genetic exchange between homologous chromosomes plays a major role in evolution by breaking linkage between advantageous and deleterious alleles in the case of introgressions. Identifying recombination rate modifiers is thus of both fundamental and practical interest to understand and utilize variation in meiotic recombination rates. We investigated recombination rate variation in a large intraspecific hybrid population (named HEB-25) derived from a cross between domesticated barley and 25 wild barley accessions. We observed quantitative variation in total crossover number with a maximum of a 1.4-fold difference between subpopulations and increased recombination rates across pericentromeric regions. The meiosis-specific α-kleisin cohesin subunit REC8 was identified as a candidate gene influencing crossover number and patterning. Furthermore, we quantified wild barley introgression patterns and revealed how local and genome-wide recombination rate variation shapes patterns of introgression. The identification of allelic variation in REC8 in combination with the observed changes in crossover patterning suggest a difference in how chromatin loops are tethered to the chromosome axis, resulting in reduced crossover suppression across pericentromeric regions. Local and genome-wide recombination rate variation is shaping patterns of introgressions and thereby directly influences the consequences of linkage drag.

Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor.

NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1ß IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.

Genome-wide association mapping in a diverse spring barley collection reveals the presence of QTL hotspots and candidate genes for root and shoot architecture traits at seedling stage.

BACKGROUND: Adaptation to drought-prone environments requires robust root architecture. Genotypes with a more vigorous root system have the potential to better adapt to soils with limited moisture content. However, root architecture is complex at both, phenotypic and genetic level. Customized mapping panels in combination with efficient screenings methods can resolve the underlying genetic factors of root traits. RESULTS: A mapping panel of 233 spring barley genotypes was evaluated for root and shoot architecture traits under non-stress and osmotic stress. A genome-wide association study elucidated 65 involved genomic regions. Among them were 34 root-specific loci, eleven hotspots with associations to up to eight traits and twelve stress-specific loci. A list of candidate genes was established based on educated guess. Selected genes were tested for associated polymorphisms. By this, 14 genes were identified as promising candidates, ten remained suggestive and 15 were rejected. The data support the important role of flowering time genes, including HvPpd-H1, HvCry2, HvCO4 and HvPRR73. Moreover, seven root-related genes, HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 are confirmed as promising candidates. For the QTL with the highest allelic effect for root thickness and plant biomass a homologue of the Arabidopsis Trx-m3 was revealed as the most promising candidate. CONCLUSIONS: This study provides a catalogue of hotspots for seedling growth, root and stress-specific genomic regions along with candidate genes for future potential incorporation in breeding attempts for enhanced yield potential, particularly in drought-prone environments. Root architecture is under polygenic control. The co-localization of well-known major genes for barley development and flowering time with QTL hotspots highlights their importance for seedling growth. Association analysis revealed the involvement of HvPpd-H1 in the development of the root system. The co-localization of root QTL with HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 represents a starting point to explore the roles of these genes in barley. Accordingly, the genes HvHOX2, HsfA2b, HvHAK2, and Dhn9, known to be involved in abiotic stress response, were located within stress-specific QTL regions and await future validation.

The JAK-STAT1 transcriptional signature in peripheral immune cells reveals alterations related to illness duration and acuity in psychosis.

Multiple lines of inquiry demonstrate alterations to immune function in psychosis. Clinically, this is reflected by elevated proinflammatory cytokines in serum, indicating activation of circulating immune cells. Data from isolated cells in clinical populations support the presence of altered activity of pertinent intracellular signaling pathways. Here, we focus on the well-characterized IFN-γ mediated JAK-STAT1 signaling pathway, which is involved in multiple aspects of immunity, including activation of circulating immune cells to a proinflammatory phenotype. By measuring a transcriptional signature characteristic of activation of this pathway, we demonstrate that JAK-STAT1 signature gene expression is suppressed in participants with psychosis who are early in illness and in participants who are hospitalized with an acute exacerbation of psychosis. Furthermore, we find that this expression signature normalizes in participants who have a longer illness duration and chronic, but not acute, psychopathology. This relationship of JAK-STAT1 signature gene expression with clinical characteristics highlights the temporal and contextual complexity of alterations to immune activity in psychosis and provides important insight into the functional state of circulating immune cells. These findings are of particular interest given recent research illustrating the importance of peripherally derived immune cells and the effectors they secrete in mediating neurophysiological processes of relevance for psychiatric illness.

Randomized phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H in the prophylactic treatment of chemotherapy-induced neutropenia.

Pegfilgrastim is indicated for reducing the duration of neutropenia and incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy. Here, safety and efficacy of MYL-1401H, a proposed pegfilgrastim biosimilar, were investigated as prophylaxis for chemotherapy-induced neutropenia. This was a phase 3, multicenter, randomized, double-blind, parallel-group equivalence trial of MYL-1401H vs European Union-sourced reference pegfilgrastim. Patients with newly diagnosed stage II/III breast cancer eligible to receive (neo) adjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide every 3 weeks for 6 cycles were enrolled and randomized 2:1 to 6 mg of MYL-1401H or reference pegfilgrastim 24 h (+ 2-h window after the first 24 h) after the end of chemotherapy. The primary efficacy endpoint was the duration of severe neutropenia in cycle 1 (i.e., days with absolute neutrophil count (ANC) < 0.5 × 109/L). Mean (standard deviation (SD)) duration of severe neutropenia in MYL-1401H and reference pegfilgrastim groups was 1.2 days (0.93) and 1.2 days (1.10), respectively. The 95% CI for least squares mean difference (- 0.285, 0.298) was within the predefined equivalence range of ± 1 day. Secondary endpoints, including grade ≥ 3 neutropenia (frequency, 91% and 82% for MYL-1401H and reference pegfilgrastim, respectively), time to ANC nadir (mean (SD), 6.2 (0.98) and 6.3 (1.57) days), and duration of post-nadir recovery (mean (SD), 1.9 (0.85) and 1.7 (0.91) days) were comparable. Overall safety profiles of the study drugs were comparable. MYL-1401H demonstrated equivalent efficacy and similar safety to reference pegfilgrastim and may be an equivalent option for reducing incidence of neutropenia. ( ClinicalTrials.gov , NCT02467868; EudraCT, 2014-002324-27).