OBJECTIVES/GOALS: RETgene fusions in sarcoma are rare and their impact on pathogenicity is unknown. Malignant peripheral nerve sheath tumors (MPNST) are a deadly, genomically heterogenous soft tissue sarcoma rarely harboring targetable aberrations. We present a case of a CCDC6-RET fusion MPNST sensitive to RET-inhibitor therapy in a xenograft model. METHODS/STUDY POPULATION: Lung tumor tissue was obtained per an approved collection protocol from a 21yo male patient with a spontaneous MPNST harboring an inactivating mutation in NF-1 and a CCDC6-RET gene fusion detected by a commercially available sequencing panel (Signatera). To confirm pathogenicity of the RET fusion, fresh tumor tissue was engrafted into immunocompromised NSG mice in the anterior and posterior flanks, harvested at ~10 weeks, and re-transplanted into bilateral flanks. When tumor diameters reached 0.5-1cm (~4 weeks), mice were randomized into 3 groups (n=6/group) and treated with either vehicle (V) (PBS), the RET-specific inhibitor selpercatinib (S) (20mg/kg twice daily), or the multi-kinase inhibitor cabozantinib (C) (30mg/kg daily) by oral gavage. Mice were monitored weekly for weight and tumor size. RESULTS/ANTICIPATED RESULTS: 92% (33/36) of implanted tumors were evaluable for treatment response. Pre-treatment tumor volumes (mm3) across all three groups were similar (mean/Std Dev – V: 230/111, S: 271/132, C: 230/123). At day 7, tumor growth was significantly inhibited by S and C versus V (ANOVA p < 0.001, post-hoc Tukey’s V vs S p= 0.0178, V vs C p< 0.0001, S vs C p= 0.0005). V-treated tumors increased in volume by 60% while S reduced tumor volume by ~80% and C reduced tumor volume by ~20%. S and C treatments were tolerated well. and S improved survival with 100% of mice alive at day 63 vs 0% in V and C groups. 6 of the 12 implanted tumors treated with S, 50% increased in size after ~6-weeks following a >90% initial tumor reduction in tumor volume. Follow-on molecular studies in S-resistant tumors are ongoing. DISCUSSION/SIGNIFICANCE: Targetable genomic changes in MPNST, especially in RET, are infrequent and often considered stochastic. Our findings suggest that precision medicine approaches pairing genomic sequencing and in vivotesting of target gene pathogenicity may guide treatment planning and novel discovery for rare, difficult to treat sarcomas.

Initial microbial colonization plays an important role in neonatal gut health. However, studies on gut microbial composition at birth are challenging, due to the limited access to accurate sampling. Here, we characterized the jejunal and ileal bacterial composition (epimural and luminal) of neonatal calves within 30 minutes after birth, and compared it with maternal (birth canal and rectum) and birth environments. RNA-based quantification along with amplicon sequencing revealed the colonization of active, dense (1.1–9.4 × 108 16S rRNA copy/g of sample), and diverse bacteria in the calf small intestine at birth. Pseudomonadaceae and Propionibacteriaceae dominated epimural communities, while Propionibacteriaceae, Prevotellaceae, Ruminococcaceae, and Lachnospiraceae dominated luminal communities. The composition of calf gut bacteria at birth was significantly different from maternal bacteria, especially for beneficial bifidobacteria. The bacterial communities of calf body habitats were similar to those of the birth environment, which was again divergent from gut microbiota. This study suggests an establishment of small intestinal-specific microbiota from birth, which is considerably deviated from maternal microbiota. In corollary, we further propose that small intestinal microbiota colonization could be mainly modulated by host selection.

The efficient separation of hexane isomers from the light naphtha fraction is a significant challenge in the petrochemical industry. 5A zeolite adsorbent is used commercially to sieve alkane isomers. In this study, 5A zeolites were synthesized using a low-cost natural clay mineral precursor, i.e. palygorskite (PAL), with the addition of crystallization directing agent (CDA). By varying the mass ratio of CDA/deionized water, 5A zeolites were obtained as CDA-5%, CDA-7.5%, and CDA-10%. All products were submicron particles with an average particle size of 400–800 nm. A sieving test of CDA-induced 5A zeolites was carried out on hexane adsorbates including n-hexane (nHEX), 2-methylpentane (2MP), and 3-methylpentane (3MP). According to vapor-phase batch adsorption experiments, a significant equilibrium amount (0.149 g/g) of nHEX and only 0.0321 g/g 2MP and 0.0416 g/g 3MP were adsorbed on the 5A zeolite product with CDA-5%. The dynamic adsorption performance of 5A zeolite (CDA-5%) was evaluated by breakthrough curves of binary mixtures of nHEX/2MP and nHEX/3MP. Palygorskite 5A (PAL 5A) zeolite achieved maximum dynamic adsorption capacities of nHEX (0.16 g/g in both cases) at 200°C and 1.2 MPa total pressure. This work provided an economic alternative for the synthesis of 5A zeolites using natural clay minerals instead of chemical raw materials.

Mechanistic studies have suggested that antioxidants have beneficial effects on age-related macular degeneration (AMD). This study aimed to investigate the association between the types and sources of dietary vitamin and carotenoid intakes and AMD risk in China. A matched case–control study of 260 AMD cases and 260 matched controls was performed. The participants were interviewed for dietary information and potential confounders, and comprehensive ophthalmic examinations were performed. Conditional logistic models were used to estimate the odds ratio (OR) and 95 % confidence interval (CI) of specific vitamins and carotenoids and their main sources. When comparing the extreme quartiles, the ORs (95 % CI) were 0·30 (0·10, 0·88) for lutein and 0·28 (0·11, 0·74) for β-cryptoxanthin. The associations for other dietary vitamin and carotenoid intakes were generally weaker and non-significant. Higher intakes of spinach and egg, which are important sources of lutein, were associated with a reduced odds of AMD. ORs (95% CIs) comparing extreme categories were 0·42 (0·20, 0·88) for spinach and 0·52 (95% CI: 0·27, 0·98) for egg. Participants who were in the highest category of both egg intake and spinach intake had a much greater reduced odds of having AMD (OR: 0·23; 95% CI: 0·08, 0·71) than those in the lowest category of egg intake and spinach intake. In conclusion, a higher intake of lutein and lutein-rich foods was associated with a significantly decreased odds of AMD. These findings provide further evidence of the benefits of lutein and lutein-rich foods in the prevention of AMD.

Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients (P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements.

For each recollement of triangulated categories, there is an epivalence between the middle category and the comma category associated with a triangle functor from the category on the right to the category on the left. For a morphic enhancement of a triangulated category $\mathcal {T}$, there are three explicit ideals of the enhancing category, whose corresponding factor categories are all equivalent to the module category over $\mathcal {T}$. Examples related to inflation categories and weighted projective lines are discussed.

We present here the first study on the stability of plane Poiseuille flow when the fluid is stratified in density perpendicularly to the plane of horizontal shear. Using laboratory experiments, linear stability analyses and direct numerical simulations, we describe the appearance of an instability that results from a resonance of internal gravity waves and Tollmien–Schlichting waves carried by the flow. This instability takes the form of long meanders confined in thin horizontal layers stacked along the vertical axis.

Prior research in the behavioral sciences has demonstrated that reminders can be an effective tool for encouraging health-related behavior changes. This article extends that literature by reporting the outcome of a randomized controlled trial of mailed vaccination reminders. In addition to making a substantive contribution regarding the efficacy of mailed reminders, this article also makes a methodological contribution: it illustrates how researchers can study the causal impact of an intervention even when a pure parallel trial is not possible. In this study, the Louisiana Department of Health sent postcard reminders regarding four recommended vaccinations (influenza, tetanus, shingles and pneumonia) to 208,867 senior residents of Louisiana. We used block randomization and a stepped wedge design to assess the efficacy of the intervention. Individuals were blocked by their prior vaccine record and randomized to receive the postcard in one of four consecutive months (October–January). The reminder postcard had an overall positive effect on vaccination rates. The statistically significant and substantively small increase in overall vaccination rates was driven by participants who received the postcard reminder early in the intervention period.

This article is a summary of perspectives on training curricula from child and adolescent psychiatry trainees globally. We aimed to identify the relative strengths, weaknesses and gaps in learning needs from a trainee's perspective. The 20 early-career child psychiatrists who contributed are from 16 countries and represent all the five continents. We could identify some global challenges as well as local/regional challenges that need to be addressed to develop competent child psychiatrists.

A greater understanding of the rumen microbiota and its function may help find new strategies to improve feed efficiency in cattle. This study aimed to investigate whether the cattle breed affects specific ruminal taxonomic microbial groups and functions associated with feed conversion ratio (FCR), using two genetically related Angus breeds as a model. Total RNA was extracted from 24 rumen content samples collected from purebred Black and Red Angus bulls fed the same forage diet and then subjected to metatranscriptomic analysis. Multivariate discriminant analysis (sparse partial least square discriminant analysis (sPLS-DA)) and analysis of composition of microbiomes were conducted to identify microbial signatures characterizing Black and Red Angus cattle. Our analyses revealed relationships among bacterial signatures, host breeds and FCR. Although Black and Red Angus are genetically similar, sPLS-DA detected 25 bacterial species and 10 functions that differentiated the rumen microbial signatures between those two breeds. In Black Angus, we identified bacterial taxa Chitinophaga pinensis, Clostridium stercorarium and microbial functions with large and small subunits ribosomal proteins L16 and S7 exhibiting a higher abundance in the rumen microbiome. In Red Angus, nonetheless, we identified the poorly characterized bacterial taxon Oscillibacter valericigenes with a higher abundance and pathways related to carbohydrate metabolism. Analysis of composition of microbiomes revealed that C. pinensis and C. stercorarium exhibited a higher abundance in Black Angus compared to Red Angus associated with FCR, suggesting that these bacterial species may play a key role in the feed conversion efficiency of forage-fed bulls. This study highlights how the discovery of signatures of bacterial taxa and their functions can be used to harness the full potential of the rumen microbiome in Angus cattle.