This study characterizes 2008-2022 FDA advisory committee discussions of new supplemental indication applications that were not approved by FDA. Discussion themes included contextual concerns unique to already-approved drugs, including insights from prior experience and concerns about off-label use, and efficacy and safety concerns also observed for new drugs. These findings highlight advisory committees’ role in transparency of regulatory decision-making, specifically for drugs already authorized for use.

Background: Over the past decade, worldwide stroke incidence has been increasing among young adults (≤65years), which has implications during the most dynamic period of their life. There is a dearth of research exploring young adults stroke patients’ experiences, healthy lifestyle habits, preferences, and recommendations for brain care-related initiatives. The study aimed to gain knowledge and a deeper understanding of young adult stroke patients’ experiences, lifestyle habits, and support needs for brain care-related education and interventions. Methods: A descriptive qualitative study was used. Participants who took part in the quantitative phase of a larger mixed methods study (n=103 that expressed an interest in the qualitative phase, were invited to take part in semi-structured focus groups. Simultaneous data collection and analysis are being conducted. Data are being analyzed using inductive thematic analysis outlined by Braun and Clarke (2006). Results: Findings will be available by May 20, 2024. Conclusions: Study findings will be essential to 1) mobilize an understanding of young adult stroke patients’ lived experience; 2) reconceptualize the current model of stroke care and services that is traditionally geared towards older adults; and 3) inform the development of brain care-related education and interventions to meet the unique needs, priorities, and preferences of young adult stroke patients.

This paper proposes a fixed-time anti-saturation (FT-AS) control scheme with a simple control loop for the 6-Degree-of-Freedom tracking (6-DOF) control problem of spacecraft with parameter uncertainties, external disturbances and input saturation. Considering the external disturbance and parameter uncertainties, the dynamical model of the tracking error is established. The traditional methods of handling input saturation usually add anti-saturation subsystems in the control system to suppress the impact of input overshoot. However, this paper directly inputs the input overshoot into the tracking error model, thus constructing a modified lumped disturbance term that includes the influence of input overshoot. Then, a novel fixed-time disturbance observer (FT-DO) is designed to estimate and compensate for this modified lumped disturbance. Therefore, there is no need to add the anti-saturation structures in the control loop, significantly reducing the complexity of the system. Finally, an observer-based fixed-time non-singular terminal sliding mode (FT-NTSM) controller is designed to guarantee the fixed-time stability of the whole system. In this way, the convergence time of the proposed scheme does not depend on the system’s initial conditions. Simulation results illustrate that the proposed method keeps the control input within the limit while achieving high-precision tracking control of attitude and position.

Competition among the two-plasmon decay (TPD) of backscattered light of stimulated Raman scattering (SRS), filamentation of the electron-plasma wave (EPW) and forward side SRS is investigated by two-dimensional particle-in-cell simulations. Our previous work [K. Q. Pan et al., Nucl. Fusion 58, 096035 (2018)] showed that in a plasma with the density near 1/10 of the critical density, the backscattered light would excite the TPD, which results in suppression of the backward SRS. However, this work further shows that when the laser intensity is so high ($>{10}^{16}$ W/cm2) that the backward SRS cannot be totally suppressed, filamentation of the EPW and forward side SRS will be excited. Then the TPD of the backscattered light only occurs in the early stage and is suppressed in the latter stage. Electron distribution functions further show that trapped-particle-modulation instability should be responsible for filamentation of the EPW. This research can promote the understanding of hot-electron generation and SRS saturation in inertial confinement fusion experiments.

We describe a new low-frequency wideband radio survey of the southern sky. Observations covering 72–231 MHz and Declinations south of $+30^\circ$ have been performed with the Murchison Widefield Array “extended” Phase II configuration over 2018–2020 and will be processed to form data products including continuum and polarisation images and mosaics, multi-frequency catalogues, transient search data, and ionospheric measurements. From a pilot field described in this work, we publish an initial data release covering 1,447 $\mathrm{deg}^2$ over $4\,\mathrm{h}\leq \mathrm{RA}\leq 13\,\mathrm{h}$ , $-32.7^\circ \leq \mathrm{Dec} \leq -20.7^\circ$ . We process twenty frequency bands sampling 72–231 MHz, with a resolution of 2′–45′′, and produce a wideband source-finding image across 170–231 MHz with a root mean square noise of $1.27\pm0.15\,\mathrm{mJy\,beam}^{-1}$ . Source-finding yields 78,967 components, of which 71,320 are fitted spectrally. The catalogue has a completeness of 98% at ${{\sim}}50\,\mathrm{mJy}$ , and a reliability of 98.2% at $5\sigma$ rising to 99.7% at $7\sigma$ . A catalogue is available from Vizier; images are made available via the PASA datastore, AAO Data Central, and SkyView. This is the first in a series of data releases from the GLEAM-X survey.

Background: Proteogenomics, the integration of proteomics and RNASeq expands the discovery landscape for candidate expressed gene networks to obtain novel insights into host response in post-infectious hydrocephalus (PIH). We examined the cerebrospinal fluid (CSF) of infants with PIH, and case controlled against age-matched infants with non-postinfectious hydrocephalus (NPIH) to probe the molecular mechanisms of PIH, leveraging molecular identification of bacterial and viral pathogens. Methods: Ventricular CSF samples of 100 infants ≤ 3 months of age with PIH (n=64) and NPIH (n=36) were analyzed with proteomics and RNASeq. 16S rRNA/DNA sequencing and virome capture identified Paenibacillus spp. and cytomegalovirus as dominant pathogenetic bacteria implicated in our PIH cohort. Proteogenomics assessed differential expression, gene set enrichment and activated gene pathways. Results: Of 616 proteins and 11,114 genes, there was enrichment for the immune system, cell-cell junction signaling and response to oxidative stress. Proteogenomics yielded 33 functionally and genetically associated gene sets related to neutrophil activation, platelet activation, and cytokines (interleukins and interferon) signaling. Conclusions: We identified PIH patients with severe disease at time of hydrocephalus surgery, to have differential expression of proteins/genes involved in neuroinflammation, ependymal barrier integrity and reaction to oxidative stress. Further studies are needed to examine those proteins/genes as biomarkers for PIH.

Frequent freezing injury greatly influences winter wheat production; thus, effective prevention and a command of agricultural production are vital. The freezing injury monitoring method integrated with ‘3S’ (geographic information systems (GIS), global positioning system (GPS) and remote sensing (RS)) technology has an unparalleled advantage. Using HuanJing (HJ)-1A/1B satellite images of a winter wheat field in Shanxi Province, China plus a field survey, crop types and winter wheat planting area were identified through repeated visual interpretations of image information and spatial analyses conducted in GIS. Six vegetation indices were extracted from processed HJ-1A/1B satellite images to determine whether the winter wheat suffered from freezing injury and its degree of severity and recovery, using change vector analysis (CVA), the freeze injury representative vegetation index and the combination of the two methods, respectively. Accuracy of the freezing damage classification results was verified by determining the impact of freezing damage on yield and quantitative analysis. The CVA and the change of normalized difference vegetation index (ΔNDVI) monitoring results were different so a comprehensive analysis of the combination of CVA and ΔNDVI was performed. The area with serious freezing injury covered 0.9% of the total study area, followed by the area of no freezing injury (3.5%), moderate freezing injury (10.2%) and light freezing injury (85.4%). Of the moderate and serious freezing injury areas, 0.2% did not recover; 1.2% of the no freezing injury and light freezing injury areas showed optimal recovery, 15.6% of the light freezing injury and moderate freezing injury areas showed poor recovery, and the remaining areas exhibited general recovery.

Background: Proteogenomics, the integration of proteomics and RNASeq expands the discovery landscape for candidate expressed gene networks to obtain novel insights into host response in post-infectious hydrocephalus (PIH). We examined the cerebrospinal fluid (CSF) of infants with PIH, and case controlled against age-matched infants with non-postinfectious hydrocephalus (NPIH) to probe the molecular mechanisms of PIH, leveraging molecular identification of bacterial and viral pathogens. Methods: Ventricular CSF samples of 100 infants ≤ 3 months of age with PIH (n=64) and NPIH (n=36) were analyzed with proteomics and RNASeq. 16S rRNA/DNA sequencing and virome capture identified Paenibacillus spp. and cytomegalovirus as dominant pathogenetic bacteria implicated in our PIH cohort. Proteogenomics assessed differential expression, gene set enrichment and activated gene pathways. Results: Of 616 proteins and 11,114 genes, there was enrichment for the immune system, cell-cell junction signaling and response to oxidative stress. Proteogenomics yielded 33 functionally and genetically associated gene sets related to neutrophil activation, platelet activation, and cytokines (interleukins and interferon) signaling. Conclusions: We identified PIH patients with severe disease at time of hydrocephalus surgery, to have differential expression of proteins/genes involved in neuroinflammation, ependymal barrier integrity and reaction to oxidative stress. Further studies are needed to examine those proteins/genes as biomarkers for PIH.

Glutamine synthetase (GS) and glutamate synthase (GOGAT) play a central role in plant nitrogen (N) metabolism. In order to study the effect of powdery mildew (Blumeria graminis f. sp. tritici, Bgt) on N metabolism, field experiments were carried out to evaluate GS and GOGAT activity, GS expression and grain protein content (GPC) in susceptible (Xi'nong 979) and resistant (Zhengmai 103) wheat cultivars under three treatments. The three treatments were no inoculation (CK), inoculated once with Bgt (MP) and inoculated nine times with Bgt (HP). For Xi'nong 979, the activities of GS and GOGAT in grains as well as GS activity in flag leaves increased at 10–15 days after anthesis (DAA), and decreased significantly at 15 or 20–30 DAA in HP and MP. However, GS activity in grains decreased from 20 DAA, which was later than that of flag leaves (15 DAA). At the same time, GS expression in grains was up-regulated at early stage, with GS1 at 10 DAA and GS2 at 15 DAA, followed by a continuous down-regulation. This result indicated that GS and GOGAT activity as well as GS expression were inhibited by powdery mildew, indicating that N metabolism in grains was inhibited at 20–30 DAA. The current study also found out that the yield of the susceptible cultivar decreased significantly, while its GPC increased obviously in HP. It was shown that the increase of GPC was not due to the enhancement of N metabolism, but due to the passive increase caused by yield reduction.

An acute gastroenteritis (AGE) outbreak caused by a norovirus occurred at a hospital in Shanghai, China, was studied for molecular epidemiology, host susceptibility and serological roles. Rectal and environmental swabs, paired serum samples and saliva specimens were collected. Pathogens were detected by real-time polymerase chain reaction and DNA sequencing. Histo-blood group antigens (HBGA) phenotypes of saliva samples and their binding to norovirus protruding proteins were determined by enzyme-linked immunosorbent assay. The HBGA-binding interfaces and the surrounding region were analysed by the MegAlign program of DNAstar 7.1. Twenty-seven individuals in two care units were attacked with AGE at attack rates of 9.02 and 11.68%. Eighteen (78.2%) symptomatic and five (38.4%) asymptomatic individuals were GII.6/b norovirus positive. Saliva-based HBGA phenotyping showed that all symptomatic and asymptomatic cases belonged to A, B, AB or O secretors. Only four (16.7%) out of the 24 tested serum samples showed low blockade activity against HBGA-norovirus binding at the acute phase, whereas 11 (45.8%) samples at the convalescence stage showed seroconversion of such blockade. Specific blockade antibody in the population played an essential role in this norovirus epidemic. A wide HBGA-binding spectrum of GII.6 supports a need for continuous health attention and surveillance in different settings.

Impairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism's heterogeneity.

Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.

A disruption database characterizing the current quench of disruptions with ITER-like tungsten divertor has been developed on EAST. It provides a large number of plasma parameters describing the predisruptive plasma, current quench time, eddy current, and mitigation by massive impurity injection, which shows that the current quench time strongly depends on magnetic energy and post-disruption electron temperature. Further, the energy balance and magnetic energy dissipation during the current quench phase has been well analysed. Magnetic energy is also demonstrated to be dissipated mainly by ohmic reheating and inductive coupling, and both of the two channels have great effects on current quench time. Also, massive gas injection is an efficient method to speed up the current quench and increase the fraction of impurity radiation.

Background: Antibiotics are among the most commonly prescribed drugs in nursing homes; urinary tract infections (UTIs) are a frequent indication. Although there is no gold standard for the diagnosis of UTIs, various criteria have been developed to inform and standardize nursing home prescribing decisions, with the goal of reducing unnecessary antibiotic prescribing. Using different published criteria designed to guide decisions on initiating treatment of UTIs (ie, symptomatic, catheter-associated, and uncomplicated cystitis), our objective was to assess the appropriateness of antibiotic prescribing among NH residents. Methods: In 2017, the CDC Emerging Infections Program (EIP) performed a prevalence survey of healthcare-associated infections and antibiotic use in 161 nursing homes from 10 states: California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee. EIP staff reviewed resident medical records to collect demographic and clinical information, infection signs, symptoms, and diagnostic testing documented on the day an antibiotic was initiated and 6 days prior. We applied 4 criteria to determine whether initiation of treatment for UTI was supported: (1) the Loeb minimum clinical criteria (Loeb); (2) the Suspected UTI Situation, Background, Assessment, and Recommendation tool (UTI SBAR tool); (3) adaptation of Infectious Diseases Society of America UTI treatment guidelines for nursing home residents (Crnich & Drinka); and (4) diagnostic criteria for uncomplicated cystitis (cystitis consensus) (Fig. 1). We calculated the percentage of residents for whom initiating UTI treatment was appropriate by these criteria. Results: Of 248 residents for whom UTI treatment was initiated in the nursing home, the median age was 79 years [IQR, 19], 63% were female, and 35% were admitted for postacute care. There was substantial variability in the percentage of residents with antibiotic initiation classified as appropriate by each of the criteria, ranging from 8% for the cystitis consensus, to 27% for Loeb, to 33% for the UTI SBAR tool, to 51% for Crnich and Drinka (Fig. 2). Conclusions: Appropriate initiation of UTI treatment among nursing home residents remained low regardless of criteria used. At best only half of antibiotic treatment met published prescribing criteria. Although insufficient documentation of infection signs, symptoms and testing may have contributed to the low percentages observed, adequate documentation in the medical record to support prescribing should be standard practice, as outlined in the CDC Core Elements of Antibiotic Stewardship for nursing homes. Standardized UTI prescribing criteria should be incorporated into nursing home stewardship activities to improve the assessment and documentation of symptomatic UTI and to reduce inappropriate antibiotic use.

Funding: None

Disclosures: None

The pandemic of coronavirus disease 2019 (COVID-19) has posed serious challenges. It is vitally important to further clarify the epidemiological characteristics of the COVID-19 outbreak for future study and prevention and control measures. Epidemiological characteristics and spatial−temporal analysis were performed based on COVID-19 cases from 21 January 2020 to 1 March 2020 in Shandong Province, and close contacts were traced to construct transmission chains. A total of 758 laboratory-confirmed cases were reported in Shandong. The sex ratio was 1.27: 1 (M: F) and the median age was 42 (interquartile range: 32–55). The high-risk clusters were identified in the central, eastern and southern regions of Shandong from 25 January 2020 to 10 February 2020. We rebuilt 54 transmission chains involving 209 cases, of which 52.2% were family clusters, and three widespread infection chains were elaborated, occurring in Jining, Zaozhuang and Liaocheng, respectively. The geographical and temporal disparity may alert public health agencies to implement specific measures in regions with different risk, and should attach importance on how to avoid household and community transmission.

The modelling of edge carbon transport and emission on EAST tokamak under resonant magnetic perturbation (RMP) fields has been conducted with the three-dimensional edge transport code EMC3-EIRENE. The measured vertical distribution of CVI emission by the extreme ultraviolet spectrometer system for the perturbed case shows a reduction in the CVI emission by 20 % compared to the equilibrium case. The chord-integrated CVI emission can be reconstructed by EMC3-EIRENE modelling, which presents an increase in the CVI emission with RMP fields. The discrepancy between experiments and simulations has been investigated by parameter study to examine the sensitivity of the simulation results on the edge plasma conditions and the impurity perpendicular transport. It is found that the variation of edge plasma conditions for the equilibrium case cannot resolve the discrepancy in the CVI emission between simulations and measurements. The simulations with enhanced impurity perpendicular transport coefficient allows a reasonable agreement with the measured reduction of CVI emission.

Ovarian follicle selection is a natural biological process in the pre-ovulatory hierarchy in birds that drives growing follicles to be selected within the ovulatory cycle. Follicle selection in birds is strictly regulated, involving signaling pathways mediated by dietary nutrients, gonadotrophic hormones and paracrine factors. This study aimed to test the hypothesis that dietary Ca may participate in regulating follicle selection in laying ducks through activating the signaling pathway of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/extracellular signal-regulated kinase (ERK), possibly mediated by gonadotrophic hormones. Female ducks at 22 weeks of age were initially fed one of two Ca-deficient diets (containing 1.8% or 0.38% Ca) or a Ca-adequate control diet (containing 3.6% Ca) for 67 days (depletion period), then all birds were fed the Ca-adequate diet for an additional 67 days (repletion period). Compared with the Ca-adequate control, ducks fed 0.38% Ca during the depletion period had significantly decreased (P < 0.05) numbers of hierarchical follicles and total ovarian weight, which were accompanied by reduced egg production. Plasma concentration of FSH was decreased by the diet containing 1.8% Ca but not by that containing 0.38%. The ovarian content of cAMP was increased with the two Ca-deficient diets, and phosphorylation of PKA and ERK1/2 was increased with 0.38% dietary Ca. Transcripts of ovarian estradiol receptor 2 and luteinizing hormone receptor (LHR) were reduced in the ducks fed the two Ca-deficient diets (P < 0.05), while those of the ovarian follicle stimulating hormone receptor (FSHR) were decreased in the ducks fed 0.38% Ca. The transcript abundance of ovary gap junction proteins, A1 and A4, was reduced with the Ca-deficient diets (P < 0.05). The down-regulation of gene expression of gap junction proteins and hormone receptors, the increased cAMP content and the suppressed hierarchical follicle numbers were reversed by repletion of dietary Ca. These results indicate that dietary Ca deficiency negatively affects follicle selection of laying ducks, independent of FSH, but probably by activating cAMP/PKA/ERK1/2 signaling pathway.

Se can enhance lactation performance by improving nutrient utilization and antioxidant status. However, sodium selenite (SS) can be reduced to non-absorbable elemental Se in the rumen, thereby reducing the intestinal availability of Se. The study investigated the impacts of SS and coated SS (CSS) supplementation on lactation performance, nutrient digestibility, ruminal fermentation and microbiota in dairy cows. Sixty multiparous Holstein dairy cows were blocked by parity, daily milk yield and days in milk and randomly assigned to five treatments: control, SS addition (0.3 mg Se/kg DM as SS addition) or CSS addition (0.1, 0.2 and 0.3 mg Se/kg DM as CSS addition for low CSS (LCSS), medium CSS (MCSS) and high CSS (HCSS), respectively). Experiment period was 110 days with 20 days of adaptation and 90 days of sample collection. Dry matter intake was higher for MCSS and HCSS compared with control. Yields of milk, milk fat and milk protein and feed efficiency were higher for MCSS and HCSS than for control, SS and LCSS. Digestibility of DM and organic matter was highest for CSS addition, followed by SS addition and then control. Digestibility of CP was higher for MCSS and HCSS than for control, SS and LCSS. Higher digestibility of ether extract, NDF and ADF was observed for SS or CSS addition. Ruminal pH decreased with dietary Se addition. Acetate to propionate ratio and ammonia N were lower, and total volatile fatty acids (VFAs) concentration was greater for SS, MCSS and HCSS than control. Ruminal H ion concentration was highest for MCSS and HCSS and lowest for control. Activities of cellobiase, carboxymethyl-cellulase, xylanase and protease and copies of total bacteria, fungi, Ruminococcus flavefaciens, Fibrobacter succinogenes and Ruminococcus amylophilus increased with SS or CSS addition. Activity of α-amylase, copies of protozoa, Ruminococcus albus and Butyrivibrio fibrisolvens and serum glucose, total protein, albumin and glutathione peroxidase were higher for SS, MCSS and HCSS than for control and LCSS. Dietary SS or CSS supplementation elevated blood Se concentration and total antioxidant capacity activity. The data implied that milk yield was elevated due to the increase in total tract nutrient digestibility, total VFA concentration and microorganism population with 0.2 or 0.3 mg Se/kg DM from CSS supplementation in dairy cows. Compared with SS, HCSS addition was more efficient in promoting lactation performance of dairy cows.