In the present study, we investigated the influence of different mid-stage N compensation timings on agronomic and physiological traits associated with grain yield and quality in field experiments. Two japonica rice cultivars with a good tasting quality (Nangeng 9108 and Nangeng 5055) were examined under eight N compensation timings (N1–N6: one-time N compensation at 7-2 weeks before heading; N7: split N compensation at 5 and 3 weeks before heading; N8: split N compensation at 4 and 2 weeks before heading) and a control with no N compensation. The highest yield was obtained with N7, followed by N3. The yield advantage is mainly attributable to the improved population structure (higher productive tiller rate with a stable number of effective panicles), higher total number of spikelets per unit area (large panicles with more grains per panicle), larger leaf area index in the late period and higher photosynthetic production capacity (more dry matter accumulation and transportation in the middle and late periods). Delaying N compensation timing improved the processing and nutritional quality of rice, but decreased the quality of appearance and cooking/eating traits. Our results suggest that, from the perspective of achieving relative coordination between high yield and high quality of japonica rice, the optimal N compensation should be divided equally at 5 and 3 weeks before heading. However, if simplifying the number of operations and the pursuit of eating quality were considered, one-time N compensation should be conducted at 5 weeks before heading.

Ascaridia galli (Nematoda: Ascaridiidae) is the most common intestinal roundworm of chickens and other birds with a worldwide distribution. Although A. galli has been extensively studied, knowledge of the genetic variation of this parasite in detail is still insufficient. The present study examined genetic variation in the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene among A. galli isolates (n = 26) from domestic chickens in Hunan Province, China. A portion of the cox1 (pcox1) gene was amplified by polymerase chain reaction separately from adult A. galli individuals and the amplicons were subjected to sequencing from both directions. The length of the sequences of pcox1 is 441 bp. Although the intra-specific sequence variation within A. galli is 0–7.7%, the inter-specific sequence differences among other members of the infraorder Ascaridomorpha were 11.4–18.9%. Phylogenetic analyses based on the maximum likelihood method using the sequences of pcox1 confirmed that all of the Ascaridia isolates were A. galli, and also resolved three distinct clades. Taken together, the findings suggest that A. galli may represent a complex of cryptic species. Our results provide an additional genetic marker for the management of A. galli in chickens and other birds.

Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.

Background: The goal of the study was to assess responder rates at various times after initiating atogepant treatment. Methods: A 12-week phase 3 trial evaluated the safety, efficacy, and tolerability of atogepant for preventive treatment of migraine (ADVANCE; NCT03777059) in adult participants with a ≥1-year history of migraine, experiencing 4-14 migraine days/month. Participants were randomized to atogepant 10, 30, or 60mg, or placebo once daily. These analyses evaluated ≥25%, ≥50%, ≥75%, and 100% reductions in mean monthly migraine days (MMDs) across 12 weeks and each 4-week interval. Adverse events (AEs) in ≥5% of participants are reported. Results: The efficacy analysis population included 873 participants: placebo: n=214; atogepant: 10mg: n=214; 30mg: n=223; 60mg: n=222. Atogepant-treated participants were more likely to experience a ≥50% reduction in the 3-month mean MMDs (56-61% vs 29% with placebo; P<0.0001). The proportions of participants experiencing ≥25%, ≥50%, ≥75%, and 100% reductions in mean MMDs significantly increased during each 4-week interval (≥50% reduction: 48-71% vs 27-47% with placebo). The most common AEs for atogepant were constipation (6.9-7.7%) and nausea (4.4-6.1%). Conclusions: Once-daily atogepant 10, 30, and 60mg significantly increased responder rates at all thresholds with approximately 60% achieving a ≥50% reduction in mean MMDs at 12 weeks.

Microfluidic systems consisting of a square microchannel with an orthogonal side branch are promising tools to enrich or sort suspensions of deformable capsules. To allow their operating control, we numerically consider a train of initially spherical identical capsules, equally spaced along the axis of the feeding channel. The capsules have a strain-hardening membrane, an internal fluid viscosity identical to that of the external fluid and a size comparable to that of the channel. We study the influence of the interspacing on the capsule path selection at the channel bifurcation using a three-dimensional immersed boundary–lattice Boltzmann method. Our objectives are to establish a phase diagram and identify the critical interspacing above which hydrodynamic interaction between capsules no longer affects their path selection. We find two main regimes. At low interspacing, strong capsule interaction leads to an unsteady regime for which the capsule path selection follows either a periodic or a disordered state. Above a critical initial interspacing $d_{ct}$, a steady regime is achieved where interaction between capsules is too weak to affect their path selection. The capsules then follow an identical steady trajectory. We find that the dependence of the interspacing $d_{ct}$, normalised by the capsule radius, on the flow split ratio falls onto a universal curve regardless of the flow strength, capsule size and membrane shear elasticity. We also compare the path selection of a capsule train with that of a two-capsule system, and discuss applications of the present results in controlling capsule trains in microfluidic suspension enrichment devices.

The vitamin B group, including riboflavin, plays paramount roles in one-carbon metabolism (OCM), and disorders related to this pathway have been linked to cancer development. The variants of genes encoding OCM enzymes and the insufficiency of B vitamins could contribute to carcinogenesis. Very few observational studies have revealed a relationship between riboflavin and gastric cancer (GC), especially under conditions of modified genetic factors. We carried out a study examining the association of riboflavin intake and its interaction with MTRR (rs1532268) genetic variants with GC risk among 756 controls and 377 cases. The OR and 95 % CI were evaluated using unconditional logistic regression models. We observed protective effects of riboflavin intake against GC, particularly in the female subgroup (OR = 0·52, 95 % CI 0·28, 0·97, Ptrend = 0·031). In the MTRR (rs1532268) genotypes analysis, the dominant model showed that the effects of riboflavin differed between the CC and CT + TT genotypes. Compared with CC carriers, low riboflavin intake in T+ carriers was significantly associated with a 93 % higher GC risk (OR = 1·93, 95 % CI 1·09, 3·42, Pinteraction = 0·037). In general, higher riboflavin intake might help reduce the risk of GC in both CC and TC + TT carriers, particularly the T+ carriers, with marginal significance (OR = 0·54, 95 % CI 0·28, 1·02, Pinteraction = 0·037). Our study indicates a protective effect of riboflavin intake against GC. Those who carry at least one minor allele and have low riboflavin intake could modify this association to increase GC risk in the Korean population.

We performed secondary analyses of a postdischarge decolonization trial of MRSA carriers that reduced MRSA infection and hospitalization by 30%. Hospitalized MRSA infection was associated with 7.9 days of non-MRSA antibiotics and CDI in 3.9%. Preventing MRSA infection and associated hospitalization may reduce antibiotic use and CDI incidence.

Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene–environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for the largest number of invasive infections due to a multidrug-resistant pathogen. Approximately 10% of hospitalized carriers will experience invasive MRSA disease in the year following discharge incurring antibiotic therapy beyond focused treatment of MRSA. Objective: We aimed to quantify the extent of non-MRSA empiric antibiotics incurred by MRSA infections and further assess the risk of Clostridioides difficile Infection (CDI) as a result of treatment of MRSA infection. Methods: The CLEAR Trial was a postdischarge randomized controlled trial of 2,121 MRSA carriers comparing MRSA education alone to education plus repeated decolonization that demonstrated a 30% reduction in MRSA infection and a 17% reduction in all-cause infection attributable to decolonization in the year following hospital discharge (Huang SS, NEJM 2019). We included all hospitalization outcomes due to MRSA infection in the CLEAR Trial with detailed medication administration records to quantify unintended consequences of MRSA infection related to empiric non-MRSA antibiotic use and resultant CDI. Full-text medical records were reviewed with a standardized abstraction form to collect inpatient administered antibiotics and hospital-associated CDI. Results: In total,154 hospitalizations due to MRSA infection with a mean length-of-stay of 10.6 days were identified. During 25 hospitalizations (16.2%), patients received only anti-MRSA antibiotics. During the remaining 129 (83.8%) hospitalizations, patients received a mean of 1.6 distinct non-MRSA antibiotics totaling a mean of 6.6 days of therapy (DOT). Empiric non-MRSA therapy was given for 3.2 DOT before MRSA culture results became available and was continued for an additional 3.4 DOT afterward. Among all 849 non-MRSA DOT, the most common were due to piperacillin-tazobactam (293 DOT, 34.5%), levofloxacin (105 DOT, 12.4%), and metronidazole (93 DOT, 11.0%). Across all 154 hospitalizations, a mean of 5.5 non-MRSA DOT was calculated per MRSA hospitalization, with 6 CDI cases (3.9%) as a direct sequelae of empiric non-MRSA antibiotics provided for MRSA infection. Conclusions: Hospitalization for MRSA infection results in extensive non-MRSA empiric antibiotic therapy both before and after MRSA culture results are known. This antibiotic use is associated with a 3.9% risk of CDI that exceeds the national risk of acquiring CDI (3.2 per 1,000 admissions) by 12-fold during any hospital stay (Barrett ML, AHRQ 2018). The CLEAR Trial findings that postdischarge decolonization reduces MRSA infection and hospitalization by 30% suggests that decolonization may also reduce non-MRSA antibiotic use and CDI in this population.

Funding: None

Disclosures: None

Over the past decades, anti-cancer treatments have evolved rapidly from cytotoxic chemotherapies to targeted therapies including oral targeted medications and injectable immunooncology and cell therapies. New anti-cancer medications come to markets at increasingly high prices, and health insurance coverage is crucial for patient access to these therapies. State laws are intended to facilitate insurance coverage of anti-cancer therapies.

Using Massachusetts as a case study, we identified five current cancer coverage state laws and interviewed experts on their perceptions of the relevance of the laws and how well they meet the current needs of cancer care given rapid changes in therapies. Interviewees emphasized that cancer therapies, as compared to many other therapeutic areas, are unique because insurance legislation targets their coverage. They identified the oral chemotherapy parity law as contributing to increasing treatment costs in commercial insurance. For commercial insurers, coverage mandates combined with the realities of new cancer medications — including high prices and often limited evidence of efficacy at approval — compound a difficult situation. Respondents recommended policy approaches to address this challenging coverage environment, including the implementation of closed formularies, the use of cost-effectiveness studies to guide coverage decisions, and the application of value-based pricing concepts. Given the evolution of cancer therapeutics, it may be time to evaluate the benefits and challenges of cancer coverage mandates.

Klebsiella pneumoniae is a common pathogen associated with nosocomial infections and is characterised serologically by capsular polysaccharide (K) and lipopolysaccharide O antigens. We surveyed a total of 348 non-duplicate K. pneumoniae clinical isolates collected over a 1-year period in a tertiary care hospital, and determined their O and K serotypes by sequencing of the wbb Y and wzi gene loci, respectively. Isolates were also screened for antimicrobial resistance and hypervirulent phenotypes; 94 (27.0%) were identified as carbapenem-resistant (CRKP) and 110 (31.6%) as hypervirulent (hvKP). isolates fell into 58 K, and six O types, with 92.0% and 94.2% typeability, respectively. The predominant K types were K14K64 (16.38%), K1 (14.66%), K2 (8.05%) and K57 (5.46%), while O1 (46%), O2a (27.9%) and O3 (11.8%) were the most common. CRKP and hvKP strains had different serotype distributions with O2a:K14K64 (41.0%) being the most frequent among CRKP, and O1:K1 (26.4%) and O1:K2 (17.3%) among hvKP strains. Serotyping by gene sequencing proved to be a useful tool to inform the clinical epidemiology of K. pneumoniae infections and provides valuable data relevant to vaccine design.