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Advances in the understanding and management of glenoid bone loss in shoulder instability have led to the development of alternative bony reconstruction techniques to the Latarjet using free bone grafts, but little is known about surgeon adoption of these procedures. This study sought to characterize surgeon variation in the use of glenoid bone reconstruction procedures for shoulder instability and ascertain reasons underlying procedure choice.A 9-question survey was created and distributed to 160 shoulder surgeons members of the PacWest Shoulder and Elbow Society, of whom 65 (41%) responded. The survey asked questions regarding fellowship training, years in practice, surgical volume, preferred methods of glenoid bone reconstruction, and reasons underlying treatment choice.All surgeons completed a fellowship, with an equal number of sports medicine fellowship-trained (46%) and shoulder and elbow fellowship-trained (46%) physicians. The majority had been in practice for at least 6 years (6-10 years: 25%;10 years: 59%). Most (78%) performed ≤10 glenoid bony reconstructions per year, and 66% indicated that bony procedures represented10% of their total annual shoulder instability case volume. The open Latarjet was the preferred primary reconstruction method (69%), followed by open free bone block (FBB) (22%), arthroscopic FBB (8%), and arthroscopic Latarjet (1%). Distal tibia allograft (DTA) was the preferred graft (74%) when performing an FBB procedure, followed by iliac crest autograft (18%), and distal clavicle autograft (6%). The top 5 reasons for preferring Latarjet over FBB were the sling effect (57%), the autologous nature of the graft (37%), its robust clinical evidence (22%), low cost (17%), and availability (11%). The top 5 reasons for choosing an FBB procedure were less anatomic disruption (58%), lower complication rate (21%), restoration of articular cartilage interface (16%), graft versatility (11%), and technical ease (11%). Only 20% of surgeons indicated always performing a bony glenoid reconstruction procedure in the noncontact athlete with less than 20% glenoid bone loss. However, that percentage rose to 62% when considering a contact athlete with the same amount of bone loss.Although open Latarjet continues to be the most popular glenoid bony primary reconstruction procedure in shoulder instability, nearly 30% of shoulder surgeons in the western United States have adopted FBB techniques as their preferred treatment modality--with DTA being the most frequently used graft. High-quality comparative clinical effectiveness research is needed to reduce decisional conflict and refine current evidence-based treatment algorithms.

PremiseEvolution of separate sexes from hermaphroditism often proceeds through gynodioecy, but genetic constraints on this process are poorly understood. Genetic (co-)variances and between-sex genetic correlations were used to predict evolutionary responses of multiple reproductive traits in a sexually dimorphic gynodioecious species, and predictions were compared with observed responses to artificial selection.MethodsSchiedea (Caryophyllaceae) is an endemic Hawaiian lineage with hermaphroditic, gynodioecious, subdioecious, and dioecious species. We measured genetic parameters of Schiedea salicaria and used them to predict evolutionary responses of 18 traits in hermaphrodites and females in response to artificial selection for increased male (stamen) biomass in hermaphrodites or increased female (carpel, capsule) biomass in females. Observed responses over two generations were compared with predictions in replicate lines of treatments and controls.ResultsIn only two generations, both stamen biomass in hermaphrodites and female biomass in females responded markedly to direct selection, supporting a key assumption of models for evolution of dioecy. Other biomass traits, pollen and ovule numbers, and inflorescence characters important in wind pollination evolved indirectly in response to selection on sex allocation. Responses generally followed predictions from multivariate selection models, with some responses unexpectedly large due to increased genetic correlations as selection proceeded.ConclusionsResults illustrate the power of artificial selection and utility of multivariate selection models incorporating sex differences. They further indicate that pollen and ovule numbers and inflorescence architecture could evolve in response to selection on biomass allocation to male versus female function, producing complex changes in plant phenotype as separate sexes evolve.

This study aims to focus on the preferences of the community regarding the adoption of stray animals in Morong, Rizal. The data collection was conducted with five (5) pet owners in each of the 8 barangays in Morong, Rizal, in 2023. Based on the findings of this study, the researchers found that the pet owner-respondents in Morong, Rizal, are most likely ready to adopt stray animals based on their preferences in terms of type, breed, condition, and color. Their reasons correspond to the subjective theory of value since they talk about how valuable the animal’s life is to them. The pet owners of Morong, Rizal who are ready to adopt mostly prefer dogs and cats, due to that they prefer types that are beneficial to the owners with good physical state and behavior (type), askal/Aspin as their most preferred breed, due to that their most preferred breeds are any breeds and breeds don’t matter to the pet owners/respondents (breed), healthy, as they want animals that ensure better living and a long lifespan (condition), mostly prefer brown color, and have color that is interesting, lovely, and color they like (color). When adopting stray animals, the respondents' choice of preferences is subjective in two (2) ways. These are what seem the basis of individuals when selecting a pet to please their satisfaction on their different judgments. The researchers will propose an advocacy campaign promoting the adoption of stray animals, specifically encouraging the attributes that are not mostly preferred in strays. The key themes from the thematic analyses of the different preferences showed that although they valued animals’ lives regardless of their kind, some tended to select them due to their appearance and benefits.

Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study.

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587

Funding Acknowledgements Type of funding sources: None. Introduction Electrical cardioversion (ECV) is an effective therapeutic alternative for atrial fibrillation (AF) and atrial flutter (AFL); however, in the medium-long term, the recurrence rate is significant and the evidence is limited. Methods Retrospective, observational, single-center, retrospective registry of 154 consecutive cases of patients undergoing electrical cardioversion for AF or AF flutter of more than 48 hours of evolution. Recurrence, emergency visits, readmissions and new ECV were recorded during a mean follow-up of 34±11 months. Results The median time from diagnosis to ECV was 60 days. The success rate of ECV was 91.7%. The immediate recurrence rate (< 2 hours) was 3.9%. The incidence of recurrence during follow-up is shown in Table 1. Of the total number of recurrences, 12.7% were detected on Holter-ECG. During follow-up, 5.8% of the patients died, none due to cardiovascular causes, 33.1% of the patients were readmitted, 25.3% due to cardiovascular causes and 15.6% as a consequence of AF/AFL. A total of 17.5% of patients attended the emergency department for episodes of AF/AFL with rapid ventricular response. Up to 18.8% of patients underwent repeat ECV and 16.2% underwent pulmonary vein ablation; in contrast, 35.3% of patients opted for a rate control strategy. Previous ECV and atrial dilatation were associated with a higher (76.9% vs 52.6% p=0.02; 64.9% vs 24% p Conclusion ECV is an effective therapy against AF and AFL, however, the recurrence rate in the medium-long term is high. Previous ECV and atrial dilatation are associated with a higher and earlier recurrence. Antiarrhythmic treatment had a neutral impact on the maintenance of sinus rhythm in the medium to long term.

Funding Acknowledgements Type of funding sources: None. Introduction Electrical cardioversion is an effective therapy for the restoration of sinus rhythm. The success of cardioversion has been related to different clinical and echocardiographic variables, although the available evidence is scarce and heterogeneous. Methods Ambispective, observational, single-center registry that consecutively included 271 patients scheduled for elective electrical cardioversion (ECV) on the inpatient ward for atrial fibrilation (AF) or flutter fibrilation (AFL) >48 hours of onset during the years 2018-2021. All patients scheduled for CVE that were ultimately discontinued on the day of the procedure were excluded, finally analyzing 244 patients. Results The baseline characteristics are shown in Picture 1. No statistically significant differences were observed in the main comorbidities, cardiovascular risk factors, CHAD2S2-VASc scale, the position of the paddles, or days to ECV between patients with successful ECV and those with a failed procedure. Neither were they observed in terms of pharmacological treatment, including the presence of previous antiarrhythmic treatment as part of a facilitated ECV strategy (Picture 2). Moderately-severely depressed systolic function and the presence of moderate-severe mitral regurgitation were associated with a higher rate of cardioversion failure (3% vs 2.6% p= 0.002; 3.3% vs 1.3% p=0.001), higher number of biphasic electric shocks (1.3 vs 1.6 p Conclusion Patients with moderate-severe systolic dysfunction and significant mitral and tricuspid regurgitation have a lower success rate of ECV. Previous antiarrhythmic therapy presents a neutral effect on sinus rhythm restoration and immediate recurrence.

Funding Acknowledgements Type of funding sources: None. Introduction and objectives The prevalence of left atrial (LA) thrombus in patients with atrial fibrillation (AF) or atrial flutter (AFL) on guideline-directed anticoagulation is nor well known, moreover, evidence on the presence of left atrial thrombus with different anticoagulation therapies provides heterogeneous results. Methods Ambispective, observational, single-center study that consecutively included 271 patients undergoing elective electrical cardioversion (ECV) for AF or AFL >48 hours of onset. A transoesophageal echocardiogram (TOE) was performed in all patients within 24 hours prior to ECV. Patients with Results The main baseline characteristics are shown in Picture 1. A total of 66.5% of the patients were receiving treatment with direct oral anticoagulants (NOAC) dabigatran (15.9%); rivaroxaban (28.3%); apixaban (31.2%) and edoxaban (23.9%). The remaining 33.5% were anticoagulated with vitamin K antagonists (VKA). Eight thrombi were detected in the left atrial appendage (prevalence 4.7%), and on 2 occasions the presence of thrombus could not be ruled out, and CVE was also suspended. No statistically significant differences were observed between the prevalence of thrombus and the type of anticoagulant (NOAC vs VKA 4.5% vs 4.9%; p= 0.56) or between the different NOACs (p=0.61). Of the 8 patients with left atrial thrombus, anticoagulant treatment was modified in 3 of them. Control TOE was performed (median until new TOE 64 days), and resolution was verified in 3 cases (all under treatment with NOAC), of which 2 patients had maintained their previous anticoagulant treatment. Conclusions Anticoagulated patients scheduled for elective ECV present a prevalence of left atrial thrombus close to 5%. No differences were observed with respect to the anticoagulation treatment received.

Supplementary Tables 1, 2, and 3

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells. Downregulation of IFNAR1 mediated by p38α kinase protected Treg cells from fragility and maintained NRP1 levels, which were decreased in response to IFN1. Genetic or pharmacologic inactivation of p38α and stabilization of IFNAR1 in Treg cells induced fragility and inhibited their immune suppressive and protumorigenic activities. The inhibitor of sumoylation TAK981 (Subasumstat) upregulated IFNAR1, eliciting Treg fragility and inhibiting tumor growth in an IFNAR1-dependent manner. These findings describe a mechanism by which intratumoral Treg cells retain immunosuppressive activities and suggest therapeutic approaches for inducing Treg fragility and increasing the efficacy of immunotherapies.

Supplementary Figure from Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment

Supplementary Data from Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment

S1. Clinical and molecular profile of gliomas by ASNS status S2. CDKN2A and ASNS KM survival plots by IDH status S3. ASNS copy-number gain compared to ASNS mRNA & protein expression S4. IDH mutation inversely correlate to ASNS copy number gain S5. GSCs and ASNS expression levels Supp Table 1. Clinical & Molecular Profile for Parental GSC604 & GSC827 cell lines

Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited.Implications:This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.

A typical classroom frequently consists of a single learner who is not all that interested in the subject at hand. Traditional classroom settings generally favor direct, unilateral instruction. According to the conventional view, learners must amass a predetermined body of information. This study aimed to evaluate the usefulness and effectiveness of the center-based learning approach in the classroom for teaching science subjects on students' academic performance after exposure to two approaches, the center-based learning approach, and the conventional approach. The study also looked at junior high school science teachers' perceptions of the center-based learning approach's effectiveness to students' learning capabilities based on the Proven Effectiveness Framework (PEF). The research employed a descriptive and quantitative approaches with a quasi- experimental research design. The total population size of the respondents are 60 Grade 10 students out from the 2 sections of San Vicente National High School. The test covered learning competencies found in the Grade 10 junior high school science curriculum. The learning competencies under the MELCs covered topics about volcanoes, earthquakes, epicenters, and mountain ranges. The assessment test consists of 50 multiple-choice questions. Based on the findings, there is a large difference in the results of the experimental group when exposed to CBLA, the mean score is 47.10 with a standard deviation of 4.87 and a p-value of 0.000. Furthermore, after the assessment in the posttest, the control group has a mean score of 30.05, resulting in being highly significant, and mastery level of the students' academic performance after the test is 60.23. This means that the perceptions of the junior high school science teachers in the said indicators were afflicted based on the criteria given. The center-based learning approach outperformed the conventional approach in producing better learning performance in teaching science subjects in junior high school levels, particularly in Grade 10.

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells. Downregulation of IFNAR1 mediated by p38α kinase protected Treg cells from fragility and maintained NRP1 levels, which were decreased in response to IFN1. Genetic or pharmacologic inactivation of p38α and stabilization of IFNAR1 in Treg cells induced fragility and inhibited their immune suppressive and protumorigenic activities. The inhibitor of sumoylation TAK981 (Subasumstat) upregulated IFNAR1, eliciting Treg fragility and inhibiting tumor growth in an IFNAR1-dependent manner. These findings describe a mechanism by which intratumoral Treg cells retain immunosuppressive activities and suggest therapeutic approaches for inducing Treg fragility and increasing the efficacy of immunotherapies.

Specific language impairment (SLI) is a common neurodevelopmental disorder (NDD) that displays high heritability estimates. Genetic studies have identified several loci, but the molecular basis of SLI remains unclear. With the aim to better understand the genetic architecture of SLI, we performed whole-exome sequencing (WES) in a single family (ID: 489; n = 11). We identified co-segregating rare variants in three new genes: BUD13, APLP2, and NDRG2. To determine the significance of these genes in SLI, we Sanger sequenced all coding regions of each gene in unrelated individuals with SLI (n = 175). We observed 13 additional rare variants in 18 unrelated individuals. Variants in BUD13 reached genome-wide significance (p-value < 0.01) upon comparison with similar variants in the 1000 Genomes Project, providing gene level evidence that BUD13 is involved in SLI. Additionally, five BUD13 variants showed cohesive variant level evidence of likely pathogenicity. Bud13 is a component of the retention and splicing (RES) complex. Additional supportive evidence from studies of an animal model (loss-of-function mutations in BUD13 caused a profound neural phenotype) and individuals with an NDD phenotype (carrying a CNV spanning BUD13), indicates BUD13 could be a target for investigation of the neural basis of language.