Development of the Sonata

Program: Domenico Scarlatti (1685-1757) Sonata in d minor K. 9 Sonata in E Major K. 20 Sonata in A minor K. 54 Sonata in A Major K. 24 Johannes Brahms (1833-1897) Sonata in C Major I. Allegro II. Andante III. Scherzo: Allegro molto e con fuoco IV. Finale: Allegro con fuoco Intermission--------------------------------- Ludwig van Beethoven (1770-1827) Sonata in D Major Op. 28 I. Allegro II. Andante III. Scherzo-Trio: Allegro vivace IV. Rondo: Allegro ma non Troppo Sergei Prokofiev (1891-1953) Sonata in f minor Op.

CBCT Evaluation of Adolescent Mandibular Morphology in Different Classifications of Facial Type

The goal of this study is to use the improved imaging capability of cone-beam computerized tomography (CBCT) to investigate the relationship between vertical facial patterns and mandibular tooth-alveolar morphology in the adolescent population. Pre-treatment orthodontic records were obtained from the UNLV School of Dental Medicine archival dental records. One hundred and seventy three patients (72 males, 101 females) between the ages of 12 and 18 years were included in this study. Among these patients, 61 displayed the vertical growth pattern, 30 displayed the horizontal growth pattern, and 82 displayed the average growth pattern. The samples were categorized into 4 age groups for analysis: Group 1 (age 12 to 18), Group 2 (age 12 to 13), Group 3 (age 14 to 15), and Group 4 (age 16 to 18). Cross sectional slices of the mandible were developed from the cone-beam scans to evaluate cortical bone thickness, alveolar bone height, alveolar bone width, tooth inclination, and alveolar bone inclination at four locations. Each cross section was measured at 10 sites, which included 5 cortical bone thickness, 1 height, 2 width, 1 tooth inclination, and 1 bone inclination measurements. An analysis of variance (ANOVA) with post-hoc Scheffé statistical analysis was used with a significance level of p \u3c 0.05. Results of this study indicated that in all age groups the hyperdivergent facial type generally had the thinnest cortical bone, the highest alveolar bone height at the anterior region of the mandible, and the narrowest alveolar bone width compared with the other two facial types. The hyperdivergent facial type had more upright lower incisor and more lingually inclined posterior teeth than the other facial types. The alveolar bone inclination generally followed the same angulation tendency as the tooth inclination. The results of this study indicates statistically significant differences exist in cortical bone thickness, alveolar bone height, alveolar bone width, tooth inclination, and bone inclination measurements between the various facial types in the adolescent population

RLVF: Learning from Verbal Feedback without Overgeneralization

The diversity of contexts in which large language models (LLMs) are deployed requires the ability to modify or customize default model behaviors to incorporate nuanced requirements and preferences. A convenient interface to specify such model adjustments is high-level verbal feedback, such as "Don't use emojis when drafting emails to my boss." However, while writing high-level feedback is far simpler than collecting annotations for reinforcement learning from human feedback (RLHF), we find that simply prompting a model with such feedback leads to overgeneralization of the feedback to contexts where it is not relevant. We study the problem of incorporating verbal feedback without such overgeneralization, inspiring a new method Contextualized Critiques with Constrained Preference Optimization (C3PO). C3PO uses a piece of high-level feedback to generate a small synthetic preference dataset specifying how the feedback should (and should not) be applied. It then fine-tunes the model in accordance with the synthetic preference data while minimizing the divergence from the original model for prompts where the feedback does not apply. Our experimental results indicate that our approach effectively applies verbal feedback to relevant scenarios while preserving existing behaviors for other contexts. For both human- and GPT-4-generated high-level feedback, C3PO effectively adheres to the given feedback comparably to in-context baselines while reducing overgeneralization by 30%.Comment: 9 pages, 9 figure

Assessing Reading Comprehension in Bilinguals

A new measure of reading comprehension, the Diagnostic Assessment of Reading Comprehension (DARC), designed to reflect central comprehension processes while minimizing decoding and language demands, was pilot tested. We conducted three pilot studies to assess the DARC’s feasibility, reliability, comparability across Spanish and English, developmental sensitivity, and relation to standardized measures. The first study, carried out with 16 second‐through sixth‐grade English language learners, showed that the DARC items were at the appropriate reading level. The second pilot study, with 28 native Spanish‐speaking fourth graders who had scored poorly on the Woodcock‐Johnson Language Proficiency Reading Passages subtest, revealed a range of scores on the DARC, that yes‐no answers were valid indicators of respondents’ thinking, and that the Spanish and English versions of the DARC were comparable. The third study, carried out with 521 Spanish‐speaking students in kindergarten through grade 3, confirmed that different comprehension processes assessed by the DARC (text memory, text inferencing, background knowledge, and knowledge integration) could be measured independently, and that DARC scores were less strongly related to word reading than Woodcock‐Johnson comprehension scores. By minimizing the need for high levels of English oral proficiency or decoding ability, the DARC has the potential to reflect the central comprehension processes of second‐language readers of English more effectively than other measures

Galectin-3 Modulates Th17 Responses by Regulating Dendritic Cell Cytokines

Galectin-3 is a β-galactoside–binding animal lectin with diverse functions, including regulation of T helper (Th) 1 and Th2 responses. Current data indicate that galectin-3 expressed in dendritic cells (DCs) may be contributory. Th17 cells have emerged as critical inducers of tissue inflammation in autoimmune disease and important mediators of host defense against fungal pathogens, although little is known about galectin-3 involvement in Th17 development. We investigated the role of galectin-3 in the induction of Th17 immunity in galectin-3–deficient (gal3−/−) and gal3+/+ mouse bone marrow–derived DCs. We demonstrate that intracellular galectin-3 negatively regulates Th17 polarization in response to the dectin-1 agonist curdlan (a β-glucan present on the cell wall of fungal species) and lipopolysaccharide, agents that prime DCs for Th17 differentiation. On activation of dectin-1, gal3−/− DCs secreted higher levels of the Th17-axis cytokine IL-23 compared with gal3+/+ DCs and contained higher levels of activated c-Rel, an NF-κB subunit that promotes IL-23 expression. Levels of active Raf-1, a kinase that participates in downstream inhibition of c-Rel binding to the IL23A promoter, were impaired in gal3−/− DCs. Modulation of Th17 by galectin-3 in DCs also occurred in vivo because adoptive transfer of gal3−/− DCs exposed to Candida albicans conferred higher Th17 responses and protection against fungal infection. We conclude that galectin-3 suppresses Th17 responses by regulating DC cytokine production

Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders.

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.MR

Efficacy and Safety of Fecal Microbiota Transplantation in Treatment of Clostridioides difficile Infection among Pediatric Patients: A Systematic Review and Meta-Analysis

Background and Aims: Cases of Clostridioides difficile infection have been rising among the pediatric and adolescent population. Fecal microbiota transplantation (FMT) has emerged as an alternative therapy for recurrent C. difficile infection. We aim to perform the first systematic review and meta-analysis investigating the safety and efficacy of fecal microbiota transplantation for C. difficile infection in children and adolescents. Methods: A literature search was performed using variations of the keywords “pediatrics”, “C. difficile infection”, and “fecal microbiota transplantation” in PubMed, EMBASE, CINAHL, Cochrane, and Google Scholar from inception to 30 June 2022. The resulting 575 articles were independently screened by three authors. Fourteen studies that satisfied the eligibility criteria were included in the meta-analysis. Results: The pooled success rate of FMT in the overall cohort was 86% (95% confidence interval: 77–95%; p \u3c 0.001; I2 = 70%). There were 38 serious adverse events in 36 patients with a pooled rate of 2.0% (95% confidence interval: 0.0–3.0%; p = 0.1; I2 = 0.0%) and 47 adverse events in 45 patients with a pooled rate of 15% (95% confidence interval: 5.0–25.0%; p = 0.02; I2 = 54.0%). There was no death associated with FMT. Conclusions: FMT was concluded to be an effective and safe therapy in pediatric and adolescent patients with C. difficile infection. Underlying comorbidities may impede the efficacy. A rigorous screening process of the donors is recommended prior to embarking on FMT. There is no universal and cost-effective way to monitor the long-term outcomes of FMT. While promising, metagenomic sequencing may not be available in settings with limited resources. Robust data from randomized clinical trials is warranted

In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes

In adoptive cell therapy (ACT), autologous tumor-specific T-cells isolated from cancer patients are activated and expanded ex vivo, then infused back into the individual to eliminate metastatic tumors. A major limitation of this promising approach is the rapid loss of ACT T-cell effector function in vivo due to the highly immunosuppressive environment in tumors. Protection of T-cells from immunosuppressive signals can be achieved by systemic administration of supporting adjuvant drugs such as interleukins, chemotherapy, and other immunomodulators, but these adjuvant treatments are often accompanied by serious toxicities and may still fail to optimally stimulate lymphocytes in all tumor and lymphoid compartments. Here we propose a novel strategy to repeatedly stimulate or track ACT T-cells, using cytokines or ACT-cell-specific antibodies as ligands to target PEGylated liposomes to transferred T-cells in vivo. Using F(ab′)[subscript 2] fragments against a unique cell surface antigen on ACT cells (Thy1.1) or an engineered interleukin-2 (IL-2) molecule on an Fc framework as targeting ligands, we demonstrate that > 95% of ACT cells can be conjugated with liposomes following a single injection in vivo. Further, we show that IL-2-conjugated liposomes both target ACT cells and are capable of inducing repeated waves of ACT T-cell proliferation in tumor-bearing mice. These results demonstrate the feasibility of repeated functional targeting of T-cells in vivo, which will enable delivery of imaging contrast agents, immunomodulators, or chemotherapy agents in adoptive cell therapy regimens.National Institutes of Health (U.S.) (CA140476)National Institutes of Health (U.S.) (CA172164)United States. Dept. of Defense (Contract W81XWH-10-1-0290)National Cancer Institute (U.S.) (Koch Institute Support (core) Grant P30-CA14051